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BARD1 binds USP15. 44 / 44
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"These results suggest that SART3 facilitates BARD1 deubiquitination via promoting USP15-BARD1 association, therefore leading to BRCA1/BARD1 retention, and eventually DNA end resection at DSBs."
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"Since USP15 interacts with BARD1 and this interaction is important for HR, we hypothesized that BARD1 is the prime target of USP15."
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"USP15 interacts with BARD1 via its C-terminal region."
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"As USP15 affects BARD1 recruitment to DSBs, we next examined whether USP15 could interact with BARD1."
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"Furthermore, the interaction between USP15 and BARD1 was confirmed by in vitro glutathione S-transferase (GST) pull-down assay."
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"USP15 deletion mutant (deletion residues 740-981) abolished the binding of USP15 with BARD1."
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"Consistent with the previous study xref , CPT treatment enhanced the USP15-BARD1 association (Fig.  xref )."
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"In addition, the YA1 mutant lost its ability to enhance the chromatin USP15-BARD1 interaction (Fig.  xref )."
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"These data suggest that SART3 facilitates the USP15-BARD1 interaction and BRAD1 retention at DSBs."
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"SART3 not only promotes DDX1 accumulation to facilitate timely removal of DNA‒RNA hybrids but also stimulates USP15-BARD1 interaction to enhance BARD1/BRCA1 retention at DSBs, thereby facilitating DNA end resection and HR (Fig.  xref )."
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"More interestingly, patients carried USP15 mutations that disrupted USP15-BARD1 interaction, and the cancer cell is more sensitive to PARP inhibitor."
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"To understand how SART3 promotes USP15-BARD1 association, we first co-transfected GFP-SART3 and Myc-BARD1 into 293T cells."
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"We found that SART3 stimulates the USP15-BARD1 interaction and BARD1 deubiquitination, which can potentially enhance BARD1/BRCA1 retention at DSBs to facilitate end resection xref , xref ."
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"The finding that inhibition of SART3 binding to DNA‒RNA hybrids can abolish its stimulatory effect on USP15-BARD1 association indicates that SART3 accumulation at DSBs is a prerequisite for this effect."
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"USP15 can directly interact with BARD1 by mediating its stability through deubiquitination, promoting the retention of BARD1/BRCA1 on DSB, increasing DSB terminal excision, and regulating HR and cance[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Furthermore, the USP15-BARD1 interaction is reduced in breast cancer cells with USP15 C-terminal mutations, which increases sensitivity of the cells to PARP inhibitors [ 141 ]."
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"Moreover, SART3 knockdown also impaired the chromatin binding of USP15 and BARD1 after CPT treatment (Fig. 7b)."
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"On the other hand, USP15 mutations can decrease USP15-BARD1 interaction and increase PARP inhibitor sensitivity in cancer cells [ 31 ]."
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"Furthermore, cancer-associated USP15 mutations, with decreased USP15-BARD1 interaction, increases PARP inhibitor sensitivity in cancer cells."
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"Nevertheless, the R836W mutant still associates with DNA–RNA hybrids to accumulate at DSBs, retaining the ability to enhance USP15-BARD1 interaction and end resection."
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"Moreover, SART3 promotes DNA end resection through enhancing USP15-BARD1 association and BRCA1-BARD1 retention."
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"At the molecular level, USP15 M861V/D967H disrupted USP15-BARD1 interaction and failed to deubiquitinate BARD1 at the BRCT domain (Fig.  xref )."
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"Moreover, USP15 C-terminal is mutated in breast cancer patients, disrupting USP15–BARD1 interaction and resulting in HR defect."
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"Moreover, SART3 knockdown also impaired the chromatin binding of USP15 and BARD1 after CPT treatment (Fig.  xref )."
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"Therefore, mutation or reduced expression of USP15 disturbes the genomic integrity, unbound USP15-BARD1 interaction, and further enhances the response to PARPi [ xref ]."
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"USP15 interacts with BARD1 via its C-terminal region."
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"Another study consistently demonstrated that USP15 could interact with BARD1, whereas deletion of its D3 domain (deletion residues 740–981), but not that of the UBL domain, abolished the binding of USP15 with BARD1 (Peng et al. 2019)."
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"As USP15 affects BARD1 recruitment to DSBs, we next examined whether USP15 could interact with BARD1."
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"As shown in Fig.  xref , endogenous USP15 and BARD1 associated with each other in cells."
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"Furthermore, the interaction between USP15 and BARD1 was confirmed by in vitro glutathione S -transferase (GST) pull-down assay (Supplementary Fig.  xref )."
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"Interestingly, USP15–BARD1 interaction was increase after IR, HU, MMC, or CPT treatment (Fig.  xref )."
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"Here, the authors show that SART3 promotes DDX1 helicase binding to DSBs for optimal DNA-RNA hybrid removal, and enhances USP15-BARD1 association for efficient DNA end resection."
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"USP15 deletion mutant (deletion residues 740–981) abolished the binding of USP15 with BARD1."
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"Importantly, USP15–BARD1 interaction is essential for HR and cancer cell response to PARP inhibitor (Fig.  xref and Supplementary Fig.  xref )."
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"Since USP15 interacts with BARD1 and this interaction is important for HR, we hypothesized that BARD1 is the prime target of USP15."
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"SART3 promotes USP15-BARD1 association and BARD1 deubiquitination."
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"Therefore, we conclude that SART3 promotes the USP15-BARD1 interaction via respective association with USP15 and BARD1, both of which are required for the stimulatory effect of SART3 on USP15-BARD1 interaction after damage."
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"Furthermore, as SART3 depletion, PARPi treatment also abolished the stimulatory effect of CPT exposure on USP15-BARD1 interaction."
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"And combination of PARPi treatment with SART3 depletion did not cause a further inhibitory effect (Supplementary Fig.  xref ), suggesting that SART3 promotes USP15-BARD1 association in a PARylation-dependent manner."
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"Mechanistically, SART3 enriched at DSBs not only promotes timely removal of DNA‒RNA hybrids by recruiting DDX1, but also stimulates the USP15-BARD1 interaction to facilitate end resection, thereby enhancing HR."
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"Notably, the R836W mutation did not impair the stimulatory effect on the association of USP15-BARD1 (Supplementary Fig.  xref ), which probably explains why the R836W mutant could partially rescue the HR defect and sensitivity to damage agents in SART3-depleted cells (Fig.  xref )."
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"We wondered whether SART3 facilitates this event by modulating USP15-BARD1 association."
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