IndraLab
Statements
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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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"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]."
sparser
"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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"In vitro experiments have previously shown that BAP1 oligomerises and BAP1–ASXL1 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 BAP1–ASXL1 or BAP1–ASXL2 complexes xref , xref ."
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"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 ASXL1-BAP1 (BRCA1-associated protein-1) complexes, and finally, the promotion of aberrant myeloid differentiation of HSC."
sparser
"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."
sparser
"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)."
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."
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"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
"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."
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 "
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
"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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"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."
sparser
"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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"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."
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"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."
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"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
"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."