Abstract
Abstract The BAL1 macro domain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lymphomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment to DNA damage sites. However, neither BBAP nor BAL1 have been directly associated with a DNA damage response (DDR) and the function of BAL1 remains undefined. DDR proteins assemble in a coordinated, sequential manner at sites of DNA breaks. The initial recruitment phase is rapid, transient and dependent upon PARylation at DNA damage sites. A second phase, which also begins within seconds but lasts for hours, includes the sequential phosphorylation of ATM, MDC1 and the RNF8-dependent ubiquitylation of multiple double-strand break (DSB) repair factors. We have now defined a direct link between the rapid and short-lived PARP1 activation and PARylation at DNA damage sites, PAR-dependent recruitment of the BAL1 macro domain-containing protein and its partner BBAP E3 ligase, local BBAP-mediated ubiquitylation and subsequent recruitment of the checkpoint mediators, 53BP1 and BRCA1. The PARP1-dependent localization of BAL1/BBAP functionally limits both early and delayed DNA damage and enhances cellular viability independent of ATM, MDC1 and RNF8. These data establish BAL1 and BBAP as bona fide DDR pathway members and directly associate PARP1 activation, BRCA1 recruitment and DSB repair. Citation Format: Qingsheng Yan, Rong Xu, Liya Zhu, Xin Cheng, Zhe Wang, John Manis, Margaraet Shipp. BAL1 and its partner E3 Ligase, BBAP, Link PARP activation, Ubiquitylation and double-strand DNA repair independent of ATM, MDC1 and RNF8. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2013-633
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