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"These data indicate that targeting hyperactivation of the ASXL1-BAP1 complex may be a potential therapeutic strategy in mutant ASXL1 -driven myeloid malignancies.The overexpression vectors used in thi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"The mammalian homologue of Calypso, BAP1, directly associates with ASXL1, and the mammalian BAP1 and ASXL1 complex was shown to possess deubiquitinase activity in vitro 39."

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"OGT improves ASXL1 stability by inducing O-GlcNAcylation at the ASXL1 Ser199 site [127], while ASXL1 interacts with and activates BAP1 [66]."

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"ASXL1 forms a complex with the deubiquitination enzyme BAP1 and removes monoubiquitin from H2AK119Ub, to derepress genes targeted by PRC1 [ xref ]."
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"The endogenous BAP1 interaction with ASXL1 was confirmed by IP and WB analysis ( Supplemental Fig. 2B )."

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"BAP1 interacts with the polycomb factors ASXL1 and 2 and its substrates HCF-1 and OGT, but the precise mechanism how its loss of function bypasses growth arrest in BRAF mutated nevi remains to be elucidated."

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"8 BAP1 interacts with ASXL1 (MIM 612990) to form the Polycomb group Repressive Deubiquitinase complex (PR-DUB)."

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"Using the same strategy, we found that human BAP1 also forms a stable complex with the N-terminal domain of human ASXL1 (ASXL1(2–365)) but not with the human PcG proteins BMI1 or RING1A ( xref , right, lanes 8–10)."

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"ASXL1 directly interacts with BAP1, KDM1A (LSD1), NCOA1 and nuclear hormone receptors (NHRs), such as retinoic acid receptors, oestrogen receptor and androgen receptor."

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"Immunoprecipitation (IP) and Western blot analyses showed that ASXL1 Y591X but not full-length ASXL1 enhanced binding of ASXL1 to BAP1 and increased its deubiquitinating activity towards mono-ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Thus, these data suggest that AKT is a non-histone targets of the ASXL1-MT/BAP1 DUB complex."

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"BAP1 and ASXL1 recruitment and activation for H2A deubiquitination."

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"As mentioned earlier, the interaction between BAP1 and ASXL1 occurs through the ASXH domain."

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"Polycomb repressor complex 1 is involved in the mono-ubiquitination of histone H2A, whereas the human ASXL1 and BAP1 complex and the Drosophila Asx and Calypso complex are involved in H2A de-ubiquitination."

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"Here we analyse the mechanism of H2A deubiquitination by the BAP1 and ASXL1 complex."

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"ASXL1-BAP1 complex was originally defined as Polycomb Repressive complex (PR-DUB) since its homologus complex in Drosophila ( Asx - Calypso ) mediate the transcriptional repression of polycomb group ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"The association between ASXL1 and BAP1 was firstGenerally, corepressors and coactivators bind to RAR and oppositely regulate RAR activity in the absence and presence reported in Drosophila, with Droso[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Reduced occupancies of H2AK119Ub around the TSS region of critical transcription factors as well as myeloid dysplasia-associated genes were also observed, indicating the hyperactivated ASXL1-BAP1 comp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Knock-in mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with HCF-1, OGT, and the polycomb group proteins ASXL1 and ASXL2 in vivo."

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"Taken together, ASXL1-BAP1 complex can either activate or repress gene transcription under different circumstances, and we also need to pay attention to the possibly various roles of mutant and wild-t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"The BAP1 and ASXL1 complex has two closely related counterparts, the UCH-L5 and RPN13 and UCH-L5 and INO80G that are present in the proteasome and in INO80 chromatin remodelling complexes respectively."

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"The BAP1 and ASXL1 complex is specific for the Polycomb site."

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"These data show that the specificity of the BAP1 and ASXL1 complex for the Polycomb site (K119) is not determined by the amino acids surrounding the scissile isopeptide bond, but at regions outside the ubiquitinated tail such as the nucleosome core."

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"BAP1 binds ASXL1 DEU similar to UCH-L5 and RPN13 DEU."

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"The sequence and functional similarity between the BAP1 and ASXL1 DEU and UCH-L5 and RPN13 DEU complexes prompted us to examine whether the BAP1 and ASXL1 complex functions in a similar fashion (XREF_FIG)."

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"In contrast, WT BAP1 bound ASXL1 DEU with a K D of 18nM (XREF_FIG and XREF_SUPPLEMENTARY)."

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"The CTE is not important for ASXL1 DEU binding though, since both full-length BAP1 and BAP1 1-710 (construct lacking the CTE) could bind ASXL1 DEU with similar affinity (XREF_FIG and XREF_SUPPLEMENTARY)."

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"Consistent with OGT being a BAP1 substrate, ubiquitylation on OGT was reduced by the BAP1 and ASXL1 complex, and this deubiquitylation was blocked when BAP1 and ASXL1 were pre-treated with the cysteine protease inhibitor N-ethylmaleimide (NEM) (XREF_FIG)."

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"Although the mammalian ASXL1 and BAP1 complex displayed DUB activity in vitro using reconstituted nucleosomes, the activity and substrate speci- ficity in vivo remains to be addressed."

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"Collectively, these results are in agreement with a previous quantitative mass spectrometry study that also suggested a 2:1 stoichiometry for the BAP1 and ASXL1 complex XREF_BIBR."

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"Surprisingly, BAP1 1-710 that only lacks the CTE compared with WT and still binds ASXL1 DEU similar to WT, had a low activity despite the presence of ASXL1 DEU (XREF_FIG and XREF_SUPPLEMENTARY)."

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"The interaction between ASXL1 and BAP1 and the ubiquitin C-terminal hydrolase (UCH) domain of BAP1 are abso- lutely required for cooperation."

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"These findings support our proposal that RA coupled RAR signaling is associated with his- tone H2B ubiquitination through cooperation between ASXL1 and BAP1 during cellular differentiation."

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"Dotted lines indicate the minimal interaction domains of ASXL1 and B (C) Direct interaction between ASXL1 and BAP1."

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"Our results indicate that it is unlikely that the BAP1 and ASXL1 complex regulates the DNA-damage response by deubiquitinating H2A at K13/15."

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"(F) Endogenous interaction between ASXL1 and BAP1."

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"An unexpected finding was the stoichiometry of the BAP1 and ASXL1 complex, that was not 1:1 in ITC analysis."

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"It may also be possible that only one subunit is active in the BAP1 and ASXL1 complex."

sparser
"BAP1 function is intimately linked with that of ASXL1 , commonly mutated in CMML, and it was recently shown that the interaction between ASXL1 and BAP1 was restored in ASXL1 -mutation corrected clones ( xref )."

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"However, the complex of truncated ASXL1 and BAP1 retained deubiquitinase activity for an extended period of time, leading to a modest increase in overall deubiquitination ( xref , right)."

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"It was documented that a stable expression of truncated, hyperactive ASXL1BAP1 complexes in a hematopoietic precursor cell line resulted in a global erasure of histone H2A ubiquitinylated at lysine 119 (H2AK119Ub), striking depletion of trimethylation of histone H3 at lysine 27 (H3K27me3), selective upregulation of a subset of genes whose promoters were marked by both H2AK119Ub and histone H3 trimethylated (H3K4me3), and the promotion of aberrant myeloid differentiation of hematopoietic progenitor cells."

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"The PR-DUB complex, which includes ASXL1 that binds BAP1 ( xref – xref ), plays key roles in brain development ( xref – xref ) and regulation of myeloid differentiation through H2AK119 deubiquitination ( xref , xref )."

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"Subsequent WB showed that BAP1 actively cleaves ubiquitin from H2B upon adding back WT ASXL1, but not its MT, demonstrating that ASXL1 binding to BAP1 is required for BAP1 activity."

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"DISCUSSION Implications of the Interaction between ASXL1 and BAP1 We previously identified ASXL1, a mammalian homolog of Drosophila Asx, which is classified into the enhancer of Trithorax and Polycomb[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Here, we describe the interaction between ASXL1 and BAP1 and the functional importance of this interaction in detail."

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"A truncation mutation of BAP1-associated protein ASXL1, frequently found in hematopoietic malignancies, confers enhanced activity of the ASXL1BAP1 complex and acts as a gain-of-function mutation to promote myeloid leukemogenesis xref , xref ."

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"Here we present data supporting a role for an ASXL1 and BAP1 complex in the deubiquitylation of mono-ubiquitylated lysine 119 on Histone H2A (H2AK119ub1) in vivo."

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"Regarding the proposed mechanism, we noted that mutated ASXL1 formed a complex with BAP1, leading to enhanced histone deubiquitylation activity."

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"Our results also demonstrated that Gametogenetin binding protein 2 inducedASXL1 to activate the deubiquitinating enzyme BAP1 in deubiquitinating H2A, while Gametogenetin binding protein 2 knockout disrupted the interaction between ASXL1 and BAP1, resulting in BAP1 localization change."

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"We provide evidence of the target of interaction between ASXL1 and BAP1, prompting further dissection of the mechanisms by which ASXL1 and BAP1 regulate transcription."

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"This interaction between ASXL1 and BAP1 was confirmed by glutathione S-transferase (GST) pull-down assays in vitro using GST-ASXL1 fragments (aa 241aeuro " 299 and 300aeuro " 370), His BAP1 I ified by[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Our comprehensive biochemical analysis of binding interfaces, activation mechanism and recruitment factors of the BAP1 and ASXL1 complex provides a framework for future work on the possible role of these larger BAP1 complexes in tumorigenesis."

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"The tumor suppressors BAP1 and ASXL1 interact to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2A lysine 119 (H2AK119Ub)."
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"Prior to the reaction the BAP1 and ASXL1 complexes were allowed to form on ice for 10-30min."

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"Given the well-documented role of BAP1 in the DNA damage response through posttranslational modifications of histones ( xref , xref ), it is likely that binding of BAP1 to mutated ASXL1 may suppress the DNA damage response pathway, causing double-strand DNA breaks to accumulate."

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"At the molecular level, ASXL1 mutation led to a gain of function of the ASXL1BAP1 deubiquitination complex and an increase in Histone H3 Ser10 phosphorylation, a marker of proliferation."

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"Furthermore, the mammalian ASXL1 and BAP1 complex was shown to exhibit H2A DUB activity in vitro using reconstituted nucleosomes."

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"At the chromatin level during differentiation, reduced ASXL1 and BAP1 bindings were concomitant with increased ubH2B and H3K4me2 occupancies, leading to the expression of Hox genes."

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"BAP1 binds ASXL1, 2, and 3, human homologs of Drosophila Polycomb group protein ASX, which is an obligate binding partner for the Drosophila BAP1 ortholog Calypso, which catalyzes the monodeubiquitylation of histone H2A at residue K119 ( xref )."

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"GGNBP2 loss disrupts ASXL1 and BAP1 interaction resulting in BAP1 localization change."

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"Here, we found that ASXL1 was not associated with BAP1 in the testis when the Ggnbp2 was knocked out, although Western blotting analysis revealed that neither ASXL1 nor BAP1 protein expression was affected in Ggnbp2KO total testis ( xref )."

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"On the other hand, as discussed further below, ASXL1 truncations have been shown to impart a gain-of-function enhancement of the histone H2A deubiquitinase activity of the ASXL1BAP1 complex [ xref ]."

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"ASXL1 forms a deubiquitinase complex with BAP1 to remove the repressive histone mark H2A lysine 119 ubiquitination (H2AK119ub). xref , xref Mutant ASXL1 stabilizes this complex to enhance the removal of H2AK119ub. xref ASXL1 also regulates the deposition of other histone marks, including H3K27me3 and H3K4me3. xref , xref Dysregulation of the epigenome by mutant ASXL1 perturbs gene expression to promote the pathogenesis of myeloid malignancies."

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"In vitro experiments have previously shown that BAP1 oligomerises and BAP1ASXL1 can form a complex with apparent 2:1 stoichiometry xref , xref , while mass spectrometry and biochemical studies have shown that the PR-DUB can consist of BAP1ASXL1 or BAP1–ASXL2 complexes xref , xref ."

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"Immunoprecipitation studies showed that the interaction between ASXL1 and BAP1 was restored in ASXL1 mutation corrected KBM5 clones."

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"In flies and humans, the Polycomb repressive deubiquitinase (PR-DUB) complex is formed through interactions of BAP1 and ASXL1 [ xref ]."

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"It does not act upon autoubiquitinated BRCA1 [XREF_BIBR, XREF_BIBR] and has only been tested against two BRCA1 and BARD1 ubiquitin ligase substrates, histone H2A and H2B, where BAP1 and ASXL1 complexes selectively disassembled mono-ubiquitinated histone H2A [XREF_BIBR]."

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"An earlier report has suggested that ASXL1 binding to BAP1 decreases the entropy significantly [XREF_BIBR] and stabilizes the BAP1 and ASXL1 complex."

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"Immunoprecipitation (IP) and Western blot analyses showed that ASXL1 Y591X but not full-length ASXL1 enhanced binding of ASXL1 to BAP1 and increased its deubiquitinating activity towards mono-ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"BAP1 interacts with the polycomb factors ASXL1 and 2 and its substrates HCF-1 and OGT, but the precise mechanism how its loss of function bypasses growth arrest in BRAF mutated nevi remains to be elucidated."

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"BAP1-ASXL2, but not ASXL1-BAP1 complexes, appears to mediate this tumor-suppressive function; overexpression of BAP1 or ASXL2, but not ASXL1, induces senescence, and deletion of the ASXM domain of ASXL2 impairs senescence (human fibroblasts IMR90 cell line) [ xref ]."

sparser
"These data indicate that targeting hyperactivation of the ASXL1-BAP1 complex may be a potential therapeutic strategy in mutant ASXL1 -driven myeloid malignancies."

sparser
"Recent studies have reported that ASXL1 mutation resulted in hyperactivity of the ASXL1-BAP1 DUB complex in haematopoietic cells, which disturbed normal haematopoiesis and promoted myeloid leukaemogen[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"In this study, we report mutually reinforcing effects between a C-terminally truncated form of mutant ASXL1 (ASXL1-MT) and BAP1 in promoting myeloid leukaemogenesis."

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"ASXL1 and ASXL2 compete for interaction with BAP1; BAP1-ASXL1 and BAP1-ASXL2 complexes have been shown to be present at similar levels in cells."

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"Perhaps developing a small molecule to stabilise PPIs in the ASXL1 and BAP1 complex could elevate the expression of PTEN and thereby tumour suppressive activity."

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"The tumor-suppressive function of the ASXL1-BAP1 axis was further highlighted by Cao et al. These investigators demonstrated that Asxl1 loss enabled IL-3 independent growth in an AML cell line (murine 32D cells) due to the increased activation of AKT resulting from the increased levels of H2AK119Ub1 (globally as well) and H3K27me3 at the Pten promoter, which maintained Pten silencing (PTEN negatively regulates the PI3K-AKT pathway)."

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"HEK293T cells and human leukaemia cell lines were infected with lentivirus carrying ASXL1 FL or ASXL1 Y591X , IP assay was performed with anti-Flag antibody, and subsequent Western blot analysis showe[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Our data demonstrated that reduced BAP1 in ASXL1 -mutant AML blast cells could suppress leukaemogenesis, which suggests that BAP1 might be a novel therapeutic target in ASXL1 -mutated myeloid malignan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Asx and its mammalian homolog ASXL1 interact with Calypso and BAP1 to form the PR and DUB complex, which deubiquitinates histone H2AK118Ub and H2AK119Ub at the Ubx PRE and promoter [XREF_BIBR]."

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"As expected, Ggnbp2 overexpression significantly rescued the H2A K119ubi level in mutant cells but did not restore the interaction of ASXL1 and BAP1, suggesting that BAP1 was in an inactivated state."

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"ASXL1 mutants were shown to impair the association of wild-type ASXL1 with BAP1 in a dominant-negative manner by sequestering the enzyme and suppressing its recruitment to the promoters of FOXK1/K2 target genes, thereby leading to the maintenance of H2AK119Ub1 levels; deleting mutated ASXL1 restored the expression of BAP1-ASXL1-FOXK1/K2 target genes that play a role in hematopoiesis and/or tumor suppression (e.g., VHL, SOCS1/2, and TXNIP)."

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"In our study, IP and Western blot analysis showed that compared with ASXL1 FL , ASXL1 Y591X dramatically increased BAP1 binding and that co-expression of ASXL1 Y591X and BAP1 dramatically reduced the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"ASXL2-BAP1 interactions have been shown to play a role in the suppression of solid tumorigenesis (e.g., human mesotheliomas and lung cancers), and ASXL2-BAP1 complexes, similar to ASXL1-BAP1 complexes, demonstrated to interact with BAP1-interacting proteins (e.g., YY1, FOXK1/2, OGT, and HCF1) [ xref ]."

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"ASXL1-BAP1 complex was originally defined as Polycomb Repressive complex (PR-DUB) since its homologus complex in Drosophila ( Asx - Calypso ) mediate the transcriptional repression of polycomb group ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Reduced occupancies of H2AK119Ub around the TSS region of critical transcription factors as well as myeloid dysplasia-associated genes were also observed, indicating the hyperactivated ASXL1-BAP1 comp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Taken together, ASXL1-BAP1 complex can either activate or repress gene transcription under different circumstances, and we also need to pay attention to the possibly various roles of mutant and wild-t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Architecture of the BAP1/ASXL1 complex bound to H2AK119Ub nucleosome."

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"How does H2AK119Ub reach the catalytic site of BAP1/ASXL1 complex?"

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"In our structure, BAP1/ASXL1 complex anchors onto the nucleosome surface using three contact points: near the nucleosomal dyad DNA, nucleosomal exit DNA, and the acidic patch."

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"Lastly, our structure explains VUS cancer mutations that may disrupt deubiquitination activity by abrogating the interaction between BAP1/ASXL1 and substrate nucleosomes.We showed the residues R699–R701 of the BAP1 DNA clamp to form important interactions with the DNA dyad and lead to the CTE, which extends towards the DNA exit."

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"It is worth noting that in this system BAP1 and ASXL1 complex mediated gene silencing, while traditionally H2A-DUBs are associated with activation of gene expression."

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"ASXL1 -MT knock-in mice show age-related expansion of phenotypic HSCs via overactivation of Akt/mTOR signaling through deubiquitination of Akt1 by the ASXL1 -MT/Bap1 complex ( xref )."

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"The mammalian homologue of Calypso, BAP1, directly associates with ASXL1, and the mammalian BAP1 and ASXL1 complex was shown to possess deubiquitinase activity in vitro."

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"ASXL1 forms a complex with BAP1 in leukemia cells, but BAP1 loss does not upregulate HoxA gene expression in hematopoietic cells."

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"Similarly, in humans BAP1 binds ASXL1 through its carboxy-terminus and deubiquitylates H2A 34."

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"Co-immunopreciptation (co-IP) studies revealed an association between ASXL1 and BAP1 in human myeloid leukemia cells wildtype for ASXL1 but not in those cells mutant for ASXL1 due to reduced and absent ASXL1 expression (XREF_FIG)."

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"Biochemical characterization of BAP1 by XREF_BIBR identified that BAP1 and ASXL1 coexist in a complex that they termed the Polycomb repressive deubiquitinase (PR-DUB) complex."

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"BAP1/ASXL1 complex and BAP1 alone were purified as previously with adaptations (28)."

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"BAP1/ASXL1 complex assembly."

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"Assembled BAP1/ASXL1 complex was dialyzed into EMSA Buffer (10 mM HEPES pH 7.5, 50 mM NaCl, 0.1 mM DTT, 5% Glycerol)."

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"Proteomic analysis of BAP1 interacting partners using this system revealed that BAP1 interacts with ASXL1 and ASXL2 in vivo as well as host cell factor 1 (HCF-1), O-GlcNAc transferase (OGT), and Forkhead box protein K1/2 (FOXK1/2)."

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"A 2-fold serial dilution (starting concentration between 1-5 μM) of BAP1/ASXL1 complex was made in EMSA Buffer."

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"Protein quantification was done using an A280 extinction coefficient of 106,660 M cm for BAP1/ASXL1 complex on a Nanodrop spectrophotometer (Thermo-Fisher)."

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"Recent data suggested that ASXL1 might interact with BAP1 to form a H2AK119 deubiquitanase however our data suggests ASXL1 loss leads to BAP1 independent alterations in chromatin state and gene expression in hematopoietic cells."

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"The PR-DUB complex, which includes ASXL1 that binds BAP1 (18–20), plays key roles in brain development (21–23) and regulation of myeloid differentiation through H2AK119 deubiquitination (19, 24)."

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"Based on the interaction between ASXL1 and BAP1, a predominant loss of polycomb repressive complex 1 (PRC1)-mediated histone de-ubiquitination was the initial expected mechanism regulating transcriptional activity in ASXL1 MT patients xref , xref ."

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"The notion that increased de-ubiquitination is facilitating the transcriptional up-regulation through enhanced activity of the ASXL1-BAP1 complex was further confirmed in different ASXL1 MT cell lines, however, a decrease in H3K27me3 was observed at the same time in this disease model xref ."

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"The BAP1 and ASXL1 complex could be a critical component of hematopoiesis as ASXL1 mutations and dysfunction are linked to human myeloproliferative and myelodysplastic disorders [XREF_BIBR], and BAP1 knockout mice develop hematological features characteristic of these diseases [XREF_BIBR]."

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"Here we determine a cryo-EM structure of human BAP1 bound to the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome."

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"We have solved a cryo-EM structure of human BAP1 bound to the ASXL1 DEUBAD domain in complex with a H2AK119Ub nucleosome."

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"ASXL1 interacts with BAP1 protein to form the human Polycomb repressive deubiquitination (PR-DUB) complex, which removes mono-ubiquitin from lysine 119 of histone H2A ( xref )."

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"Following the reviewers’ suggestions, we have conducted additional experiments to assess the endogenous interaction of BAP1-ASXL proteins by co-immunoprecipitating reciprocally BAP1-ASXL1 and BAP1-ASXL2 in stem cell conditions (new Figure 5C and Figure 5—figure supplement 1C)."

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"Whereas knockout of Asxl1 in mice drives an MDS-like phenotype characterized by increased H3K27me and derepression of Hoxa genes ( xref , xref ), ASXL1 truncating mutations are thought to be gain of function ( xref ) and stabilize interactions between ASXL1 and BAP1 ( xref – xref )."

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"ASXL1 binds a deubiquitinase BAP1 to form a critical complex for H2A K119 deubiquitination through the catalysis of polycomb repressive complex 1 [ xref , xref ]."

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"They demonstrated that mutated ASXL1-BAP1 complex deubiquinated and stabilized AKT, which enhanced signaling through the AKT/mTOR pathway and induced aberrant cell cycle progression and proliferation of HSC/HPCs as well as abnormal mitochondrial activation, overproduction of ROS, and increased DNA damage."

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"The purified BAP1 and ASXL1 complex was shown to deubiquitinate Histone H2A but not Histone H2B in reconstituted nucleosomes [XREF_BIBR]."

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"Human wild-type ASXL1 associates with the calypso ortholog BAP1 [ xref ]."

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"ASXL1 forms a complex with BAP1 in leukemia cells, but BAP1 loss does not upregulate HoxA gene expression in hematopoietic cells."

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"Mammalian ASXL1 forms a protein complex in vitro with the chromatin deubiquitinase BAP1, which removes monoubiquitin from histone H2A at lysine 119 (H2AK119) ( xref )."

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"Immunoprecipitation of FLAG-tagged wildtype ASXL1 and FLAG-tagged leukemia-associated mutant forms of ASXL1 revealed reduced interaction between mutant forms of ASXL1 and endogenous BAP1 ( xref )."

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"Truncated ASXL1-BAP1 complexes confer gain-of-function on H2AK119Ub1-DUB activity that leads to decreases in H3K27me3 levels and the activation of normally silenced genes, as well as deubiquitination of AKT, which enhances signaling through the AKT/mTOR pathway to stimulate the proliferation of HSC/HPCs."

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"We assembled this mutated BAP1 with ASXL1, and tested catalytic activity of the resulting complex by performing DUB assays on a H2AK119Ub designer nucleosome substrate, observing a significant loss of activity relative to WT (~84%; xref , right, and xref )."

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"Scheuermann et al. [52] have shown that ASXL1 and BAP1 form a complex, termed Polycomb repressive de-ubiquitinase (PR-DUB)."

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"Recent data suggested that ASXL1 might interact with BAP1 to form a H2AK119 deubiquitanase ( xref ) however our data suggests ASXL1 loss leads to BAP1-independent alterations in chromatin state and gene expression in hematopoietic cells."

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"BAP1 binds ASXL1, 2, and 3, human homologs of Drosophila Polycomb group protein ASX, which is an obligate binding partner for the Drosophila BAP1 ortholog Calypso, which catalyzes the monodeubiquitylation of histone H2A at residue K119."

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"In addition to having activities to promote PRC2-mediated gene repression, xref ASXL1 also associates with BRCA1 associated protein 1 (BAP1) to form the canonical polycomb repressive deubiquitinase (PR-DUB) complex responsible for the removal of the repressive mark ubiquitin from histone H2A. xref Thus, ASXL1 appears to have both silencing and enhancing effects on chromatin structure."

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"Recently, it has also been shown that BAP1 is the human counterpart of the Drosophila PcG gene calypso and that the Calypso and ASX complex corresponds functionally to the human BAP1 and ASXL1 complex, representing a Polycomb repressive deubiquitinase (PR-DUB) complex 14."

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"Wildtype ASXL-1 may also interact with BAP-1 to form a deubiquitinase specific to H2AK119 which results in repression of gene transcription [XREF_BIBR]."

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"These findings raise the possibility that myeloid transformation resulting from ASXL1 and BAP1 loss could be independent of the function of the BAP1ASXL1 complex ( xref E)."

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"Regarding the proposed mechanism, we noted that mutated ASXL1 formed a complex with BAP1, leading to enhanced histone deubiquitylation activity."

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"Given the well-documented role of BAP1 in the DNA damage response through posttranslational modifications of histones (46, 47), it is likely that binding of BAP1 to mutated ASXL1 may suppress the DNA damage response pathway, causing double-strand DNA breaks to accumulate.Second, our Asxl1-mutant macrophage experiments demonstrated both pro- and antiinflammatory properties, a feature of Asxl1 that has been previously reported in zebrafish by Avagyan et al. (41)."

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"BAP1/ASXL1-nucleosome interactions are required for H2AK119Ub deubiquitination in mESCs."

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"Additionally, the silencing targets of the ASXL1 and BAP1 complex should be determined."

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"A truncation mutation of BAP1-associated protein ASXL1, frequently found in hematopoietic malignancies, confers enhanced activity of the ASXL1BAP1 complex and acts as a gain-of-function mutation to promote myeloid leukemogenesis ."

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"In our structural analysis, the neighboring residues of mutation D672 were found to be directly involved in ASXL1-BAP1 interactions; hence, alterations in the activity of PR-DUB complex can be predicted."

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"Although ASXL1 mutations are considered as a loss of function that can be mimicked using an RNAi approach, a recent study demonstrated that the ASXL1-truncated protein may act as a gain of function in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Given the fact that ASXL1 is often hyperactivated as results of gain-of-function mutations in myeloid neoplasms [ 89 , 90 ],this is reflected in the reported stability and activation of the BAP1/ASXL1[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"BAP1 binds ASXL1 DEU similar to UCH-L5/RPN13 DEU ."

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"In contrast, WT BAP1 bound ASXL1 DEU with a K D of 18 nM ( xref and xref )."

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"To test this we compared the activity of the ULD anchor mutant of BAP1 (D663A/R667A referred to as DR) bound to ASXL1 DEU to the WT complex on two substrates, K119 mono-ubiquitinated oligonucleosomal H2A and Ub-AMC."

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"The CTE is not important for ASXL1 DEU binding though, since both full-length BAP1 and BAP1 1–710 (construct lacking the CTE) could bind ASXL1 DEU with similar affinity ( xref and xref )."

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"While the UCH-L5/RPN13 complex is equimolar at 1:1, the ligand number in our ITC analysis (between 0.25 and 0.5) suggests that the BAP1/ASXL1 DEU complex is asymmetric and consists of multiple BAP1 molecules bound to one ASXL1 DEU molecule."

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"Our results also demonstrated that Gametogenetin binding protein 2 inducedASXL1 to activate the deubiquitinating enzyme BAP1 in deubiquitinating H2A, while Gametogenetin binding protein 2 knockout disrupted the interaction between ASXL1 and BAP1, resulting in BAP1 localization change."

reach
"At the endogenous level, truncated ASXL1 proteins resulting from ASXL1 mutations are rapidly degraded, and the ASXL1-BAP1 complex is undetectable (7)."

reach
"GGNBP2 loss disrupts ASXL1 and BAP1 interaction resulting in BAP1 localization change."

reach
"In WT cells, the levels of ASXL1 and BAP1 were found to be high in pachytene spermatocyte nuclei, the subcellular compartment where the ASXL1/BAP1 complex regulated H2A deubiquitination (Figure 3(h,i))."

reach
"The results showed that GGNBP2 loss reduced deubiquitinase activity by disrupting ASXL1/BAP1 binding and preventing BAP1 from entering the nucleus."

sparser
"Disruption of the coiled-coil interface does not affect the inherent catalytic activities of Calypso-Asx or BAP1-ASXL1, but impairs Calypso or BAP1 recruitment to nucleosomes [ xref ]."

sparser
"As a result, we found that both MBD5 (Fig. xref E) and MBD6 (Fig. xref F) interact with the C-terminus of ASXL1, while BAP1 interacts with ASXL1 N-terminus, which is consistent with previously reported studies [ xref ]."

reach
"By contrast, overexpression of truncated ASXL1 increases the stability of BAP1 and enhances the deubiquitination activity of ASXL1-BAP1 complex."

reach
"Western blotting with H2A antibody indicated that overexpressing Ggnbp2 did not restore the binding between ASXL1 and BAP1, and deubiquitinase BAP1 was not activated (Figure 5(d))."

reach
"Our findings showed that GGNBP2, ASXL1 and BAP1 could together form a complex."

reach
"Without GGNBP2 interaction, the binding between ASXL1 and BAP1 would be disrupted."

reach
"As expected, Ggnbp2 overexpression significantly rescued the H2A level in mutant cells but did not restore the interaction of ASXL1 and BAP1, suggesting that BAP1 was in an inactivated state."

reach
"These findings raise the possibility that myeloid transformation resulting from ASXL1 and BAP1 loss could be independent of the function of the BAP1ASXL1 complex (Fig. 3E)."

reach
"BAP1 and ASXL1 recruitment and activation for H2A deubiquitination."

reach
"Structures of the yeast SAGA DUBm (Morgan et al., 2016) and the BAP1/ASXL1 complex (Ge et al., 2023; Thomas et al., 2023) both demonstrated that nucleosome features such as the acidic patch or DNA can be critical for enzyme binding and specificity."

sparser
"NEF mutations do not impair binding of ASXL1 to BAP1, but rather impair the activity of BAP1."

sparser
"Recent work has revealed that ASXL1 regulates histone modifications through the interaction of ASXL1 and a histone deubiquitinase, BRCA1 associated protein 1 (BAP1)."

reach
"These DEUBAD sequences cover essentially the entire RPN13 CTD and NFRKB NTD structures of our UCH37 complexes, which strongly implies that the corresponding DEUBAD residues of ASXL1 will bind BAP1 in the same manner as the first 5 helices of RPN13 CTD and NFRKB NTD."

reach
"Interestingly, ASXL1 is a cofactor essential for the enzymatic activity of BAP1, and coimmunoprecipitation assays showed that ASXL1 forms a complex with BAP1 in human myeloid leukemia cells that are wild-type for ASXL1."

reach
"Here we demonstrate that ASXL1 truncations confer enhanced activity on the ASXL1 and BAP1 complex."

reach
"In bone marrow precursors, expression of truncated ASXL1 and BAP1 complex cooperates with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo."

sparser
"Ultimately, the complex of mutated ASXL1 and BAP1 leads to gain-of-function synergistic interactions between the two proteins and is thought to confer a myeloid differentiation block by deubiquitinating H2AK119 located at HOX gene regions [ xref ]."

sparser
"We further analyzed for the co-localization of BAP1 binding with independently mapped binding sites of the major BAP1-interacting proteins ASXL1 ( Li et al., 2017; Kweon et al., 2019; Nagase et al., 2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Despite evidence of clear physical interaction between ASXL1, ASXL2, and BAP1 as well as ASXL1 and the core PRC2 member SUZ12, interaction between ASXL2 and PRC2 members were not evident (XREF_SUPPLEMENTARY)."

sparser
"ASXL1 mutations in vitro studies could enhance the de-ubiquitinase activity of the ASXL1BAP1 (BRCA associated protein 1) complex, which then may cooperate with loss of TET2 to skew towards myeloid development [ xref ]."

sparser
"ASXL1 interacts with BAP1 to form a polycomb deubiquitinase complex that removes monoubiquitin from histone H2AK119. xref Through interaction with the PRC2 complex loss of Asxl1 results in a genome-wide reduction in H3K27 trimethylation. xref Asxl1 deletion excludes Ezh2 and consequently diminishes H3K27me3 at the HoxA cluster and thereby activates HoxA gene expression. xref Constitutive loss of Asxl1 had no major impact on hematopoiesis and did not induce MDS in mice. xref However, conditional knockout of Asxl1 caused progressive multilineage cytopenias and dysplasia with increased numbers of hematopoietic stem and progenitor cells reminiscent of MDS xref , xref likely mediated by HOXA9 and miR-125a activation and reduction of the miR-125a target gene CLEC5a . xref "

reach
"Here we identify leukemia associated ASXL1 mutations that aberrantly enhance the DUB activity of the ASXL1 and BAP1 complex."

reach
"Further, we establish that the ability of the hyperactive ASXL1 and BAP1 complex to deplete H3K27me3 is absolutely dependent on the catalytic activity of BAP1, indicating that H2AK119Ub plays an essential role in either recruiting or retaining the PRC2 complex at some genomic locations."

reach
"By generating bone marrow chimeras, we demonstrate that the hyperactive ASXL1 and BAP1 complex cooperates with loss of TET2 to skew lineage commitment of haematopoietic cells to the myeloid lineage."

reach
"Although ASXL1 mutations are considered as a loss of function that can be mimicked using an RNAi approach, a recent study demonstrated that the ASXL1-truncated protein may act as a gain of function in[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"An earlier report has suggested that ASXL1 binding to BAP1 decreases the entropy significantly [ xref ] and stabilizes the BAP1ASXL1 complex."

reach
"BAP1 also interacts with ASXL1 to form the Polycomb group repressive deubiquitinase complex (PR-DUB), which is involved in stem cell pluripotency and other developmental processes."

reach
"Although loss of H2AK119Ub was apparent on day 1 post transduction, loss of H3K27me3 was not apparent till day 2 post transduction (XREF_SUPPLEMENTARY), indicating that sustained expression of hyperactive ASXL1 and BAP1 complex is necessary to promote depletion of H3K27me3."

sparser
"Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways."

reach
"Third, in bone marrow chimeras in vivo, the hyperactive ASXL1 and BAP1 complex cooperated with loss of TET2 to promote commitment of haematopoietic cells to the myeloid lineage, consistent with the fact that combined mutations of ASXL1 (encoding truncated versions of ASXL1 protein) and TET2 (encoding loss-of-function mutants) are frequently observed in myeloid disorders XREF_BIBR XREF_BIBR including MDS, myeloproliferative neoplasms, systemic mastocytosis, chronic myelomonocytic leukemia and acute myeloid leukemia."

reach
"BAP1 function is intimately linked with that of ASXL1, commonly mutated in CMML, and it was recently shown that the interaction between ASXL1 and BAP1 was restored in ASXL1-mutation corrected clones (Valletta et al, 2015)."

reach
"Although the hyperactive ASXL1 and BAP1 complex clearly targets H2AK119Ub, our studies do not rule out the possibility that it also removes ubiquitin from some other substrate (s) to promote loss of H3K27me3, diminishes the multipotency of EML cells and/or alters their propensity to differentiate."

sparser
"ASXL1 binds to BAP1 and stimulates BAP1’s substrate binding affinity and activity to oppose PRC1 (polycomb repressive complex 1)-catalyzed H2AK119 monoubiquitylation, thereby releasing the polycomb repression (Scheuermann et al., xref ; Dey et al., xref ; Sahtoe et al., xref )."

sparser
"Although ASXL1 interacts with BAP1, loss of BAP1 had opposite effects than loss of ASXL1, as it resulted in increased H3K27 trimethylation, elevated expression of EZH2 and repression of PRC2 target genes. xref Thus, inhibition of BAP1 may be an interesting target in patients with mutated ASXL1 or repressed EZH2."

reach
"The authors suggested that in addition to functioning as the obligate regulatory subunit of the ASXL1 and BAP1 complex, ASXL1 might also directly regulate the deposition and/or removal of H3K27me3."

reach
"Thus, BAP1 binding ASXL1 may act to inhibit the repressive activities of PRC2 and promote gene expression."

reach
"Here we document that the ability of the hyperactive ASXL1 and BAP1 complex to deplete H3K27me3 was contingent on the catalytic activity of BAP1."

sparser
"Interestingly, ASXL1 is a cofactor essential for the enzymatic activity of BAP1, and coimmunoprecipitation assays showed that ASXL1 forms a complex with BAP1 in human myeloid leukemia cells that are wild-type for ASXL1 ."

sparser
"Mechanistically, ASXL1 forms a complex with BAP1 for the erasure of mono-ubiquitylation at lysine 119 on Histone H2A (H2AK119ub1), a well-known histone mark associated with transcription repression."

reach
"XREF_BIBR demonstrated that ASXL1 mutations resulted in loss of PRC2 mediated H3K27 tri methylation, while Balasubramani et al. 11 demonstrated that ASXL1 truncations conferred enhanced activity on the ASXL1 and BAP1 complex."

sparser
"ASXL1 directly binds to BAP1 through the ASXH domain and its adjoining region (also called deubiquitinase adaptor, DEUBAD; xref ; xref )."

sparser
"Importantly, we found that genetic deletion of the C-terminally truncated ASXL1 allele (referred to as ASXL1 +/− ), significantly increased the endogenous protein association of wild-type ASXL1 with BAP1 by as much as 2 folds compared to the corresponding control ASXL1 +/N590 K562 and ASXL1 +/N646 Kasumi-1 (Fig.  xref E and xref F)."

sparser
"Taken together, these findings suggest that C-terminally truncated mutant ASXL1 proteins are highly expressed in leukemia cells and impair the association of wild-type ASXL1 with BAP1 in a dominant-negative manner."

sparser
"Hence it is surprising that ASXL1-BAP1 or PR-DUB is genetically defined as a repressive complex."

sparser
"H2AK119 mono-ubiquitylation can be reversed by the BAP1-ASXL1 deubiquitylase (PR-DUB) ( xref , xref )."

reach
"Taken together, these results show that the BAP1 and ASXL1 complex in both humans and flies functions in repressing Hox gene expression, although the precise temporal epigenetic modifications differ between organisms."

reach
"ASXL1 binds a deubiquitinase BAP1 to form a critical complex for H2A K119 deubiquitination through the catalysis of polycomb repressive complex 1 [XREF_BIBR, XREF_BIBR]."

sparser
"Will the ASXL1-BAP1 complex regulate downstream gene expression via interaction with other TFs, in addition to FOXK1 and FOXK2?"

sparser
"At the endogenous level, truncated ASXL1 proteins resulting from ASXL1 mutations are rapidly degraded, and the ASXL1-BAP1 complex is undetectable ( xref )."

sparser
"Future work is warranted to determine whether disruption of the interaction between truncated ASXL1 and BAP1 can circumvent the oncogenic effects of increased BAP1 activity in ASXL1 truncation-driven abnormal hematopoiesis and myeloid malignancy."

sparser
"By contrast, overexpression of truncated ASXL1 increases the stability of BAP1 and enhances the deubiquitination activity of ASXL1-BAP1 complex."

reach
"The endogenous BAP1 interaction with ASXL1 was confirmed by IP and WB analysis ( Supplemental Fig. 2B )."

reach
"The architecture of the BAP1/ASXL1 complex bound to H2AK119Ub nucleosome."

reach
"We next asked how H2AK119Ub reaches the catalytic site of BAP1/ASXL1 complex."

reach
"In our structure, BAP1/ASXL1 complex anchors onto the nucleosome surface at three contact points: near the dyad DNA, exit DNA, and the acidic patch."

reach
"Last, our structure explains VUS cancer mutations that may disrupt deubiquitination activity by abrogating the interaction between BAP1/ASXL1 and substrate nucleosomes.We showed that residues R699 to R701 of the BAP1 DNA clamp form important interactions with the DNA dyad and lead to the CTE, which extends toward the DNA exit."

reach
"UCH-L5 forms a 1:1 complex with Rpn13 and INO80G DEUBADs; in contrast, experimental data suggest a 2:1 ratio for the BAP1 and ASXL1 complex [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

sparser
"ASXL1 interacts with binding partner BAP1 however there is no evidence supporting mutations of BAP1 being implicated in myeloid malignancies [ xref ]."
| PMC

sparser
"BAP1/ASXL1-nucleosome interactions are required for H2AK119Ub deubiquitination in mESCs."

sparser
"The Drosophila PR-DUB crystal structures gave context for those cancer-associated mutations in BAP1-ASXL1 that affect intramolecular contacts within the heterodimer and with Ub but gave no insight to interactions of the deubiquitinase with a H2AK119Ub nucleosome substrate ( xref , xref )."

sparser
"In addition, close interactions between BAP1 and other epigenetic regulators, such as ASXL1, emphasize the importance of BAP1 in myeloid malignancies ."

reach
"ASXL1 forms a complex with BRCA1 associated protein 1 (BAP1) that physically interacts with PRC2 and deubiquitinylates histone H2A [XREF_BIBR]."
| PMC

sparser
"These data suggest that the predicted AB box of ASXL2 is the minimal domain for binding to BAP1 and stimulating its ubiquitin hydrolase activity, and are also consistent with BAP1’s association with ASXL1 (2–365 aa) ( xref )."

reach
"The Drosophila ASXL1 homolog Asx and the BAP1 homolog Calypso form a complex which removes H2AK119Ub 7."

reach
"Key features of the BAP1 and ASXL1 complex that can not be modeled based on the UCH-L5 and DEUBAD structures are the C-terminal extension (CTE) of BAP1 (significantly longer than the UCH-L5 CTE, which is absent from the UCH-L5 crystal structures) and the additional inserted region between the strands of the coiled coil (XREF_FIG)."

sparser
"We have solved a cryo–electron microscopy (cryo-EM) structure of human BAP1 bound to the ASXL1 DEUBAD in complex with a H2AK119Ub nucleosome."

sparser
"We assembled this mutated BAP1 with ASXL1 and tested the enzymatic activity of the resulting complex by DUB assays with a H2AK119Ub designer nucleosome (dNuc) substrate, observing a substantial reduction relative to wild type (WT) (~84%; xref , right, and fig."

reach
"This activity is influenced by BAP1 binding to ASXL1."

reach
"However, the BAP1 and ASXL1 complex has not been shown to have a role in BAP1-mutant transformation."

reach
"Mechanistically, ASXL1 forms a complex with BAP1 for the erasure of mono-ubiquitylation at lysine 119 on Histone H2A (H2AK119ub1), a well-known histone mark associated with transcription repression."

reach
"We investigated which BAP1 protein binding partners, and thus which regulatory complexes, mediate TRAIL sensitivity identifying the BAP1 and ASXL1 complex, the Polycomb repressive deubiquitinase (PR-DUB), as key."

sparser
"Restoration of ASXL1-BAP1 interaction."

sparser
"Mammalian ASXL1 forms a protein complex in vitro with the tumour suppressor BAP1, a chromatin deubiquitinase that plays a role in the regulation of the cell cycle, cellular differentiation, and cell death [ xref ]."

sparser
"Immunoprecipitation studies showed that the interaction between ASXL1 and BAP1 was restored in ASXL1 mutation-corrected KBM5 clones (Figure xref )."

sparser
"Therefore, Asxl1 and Bap1 bind to and deubiquitylate H2AK119 at the Pten promoter in response to the cytokine deprivation."

sparser
"It is well-recognized that ASXL1 and BAP1 specifically form the H2AK119 deubiquitylase complex, though it still remains controversial whether the complex promotes ( xref ; xref ) or opposes ( xref ) Polycomb repressive functions."

reach
"EZH2 is an H3K27 methyltransferase that is the catalytic component of polycomb repressive complex 2 (PRC2); ASXL1 is the regulatory subunit of the ASXL1 and BAP1 complex, a deubiquitinase for H2AK119Ub [XREF_BIBR, XREF_BIBR]."

reach
"Asxl1 deletion and forced expression of Asxl1 mutations induced global reduction of H3K27me3, upregulation of Hox genes,26, 27, 59 and promote development of MDS and AML in combination with Tet mutations,59 Nras mutations,26, 27 and SETBP1 mutations.62 Bap1 is an Asxl1 binding partner, and Bap1 deletion in adult mice also caused MDS like diseases.63 These findings indicate the important role of Asxl1 and Bap1 complex to suppress myeloid transformation."

sparser
"Thus, we analyzed the roles of the hyperactive complex formed by mutant ASXL1 and the deubiquitinase BAP1 in promoting myeloid leukemogenesis."

sparser
"The mutant ASXL1-BAP1 hyperactive complex impaired the multi-lineage differentiation of hematopoietic progenitor cells and accelerated myeloid leukemogenesis."

reach
"Additionally, ASXL1 interacts with BRCA1 associated protein 1 (BAP1), creating the polycomb group repressive deubiquitinase complex, which globally removes monoubiquitin from H2AK119 and locally at HOXA and IRF8 in HSCs [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

reach
"ASXL1 forms a complex with the deubiquitination enzyme BAP1 and removes monoubiquitin from H2AK119Ub, to derepress genes targeted by PRC1 [XREF_BIBR]."
| PMC

reach
"Under physiological conditions, additional sex combs like 1 (ASXL1) can bind to BAP1 which subsequently binds to chromatin by interacting with FOXK2 (20, 47)."

sparser
"The biological consequences of the variant acquisition by hematopoietic stem cells (HSC) seem to be similar to other mutations of ASXL1 responsible for the truncation of ASXL1 protein, formation of hyperactive ASXL1BAP1 (BRCA1‐associated protein‐1) complexes, and finally, the promotion of aberrant myeloid differentiation of HSC."

sparser
"Affecting the canonical acceptor splice site at intron 12, the variant results in full retention of intron 12 and truncated protein lacking C‐terminus. xref On the basis of the literature data, the ASXL1 truncations might act as gain‐of‐function mutations, changing the function of the ASXL1BAP1 (BRCA1‐associated protein‐1; ubiquitin carboxy‐terminal hydrolase) complex."

sparser
"It was documented that a stable expression of truncated, hyperactive ASXL1BAP1 complexes in a hematopoietic precursor cell line resulted in a global erasure of histone H2A ubiquitinylated at lysine 119 (H2AK119Ub), striking depletion of trimethylation of histone H3 at lysine 27 (H3K27me3), selective upregulation of a subset of genes whose promoters were marked by both H2AK119Ub and histone H3 trimethylated (H3K4me3), and the promotion of aberrant myeloid differentiation of hematopoietic progenitor cells. xref , xref "

sparser
"Recently, we and others have shown that the mutant ASXL1 interacts with a deubiquitinase BAP1 to form the Polycomb-repressive deubiquitinase (PR-DUB) complex, which efficiently deubiquitinates H2AK119Ub xref , xref ."

sparser
"Perhaps developing a small molecule to stabilise PPIs in the ASXL1BAP1 complex could elevate the expression of PTEN and thereby tumour suppressive activity."

sparser
"It is especially evident in the light of the recently published data concerning a possible targeted therapeutic approach for ASXL1 ‐mutated leukemia through the inhibition of ASXL1BAP1 catalytic activity. xref The above‐mentioned strategy may delay the disease evolution to fibrotic phase, which itself is now considered an independent risk factor for a rapid blast progression of MPN. xref , xref "