BAL1 and Its Partner E3 Ligase, BBAP, Link Poly(ADP-Ribose) Activation, Ubiquitylation, and Double-Strand DNA Repair Independent of ATM, MDC1, and RNF8

Abstract

The BAL1 macrodomain-containing protein and its partner E3 ligase, BBAP, are overexpressed in chemotherapy-resistant lym- phomas. BBAP selectively ubiquitylates histone H4 and indirectly promotes early 53BP1 recruitment toDNAdamage sites. However, neither BBAP nor BAL1 has been directly associated with aDNAdamage response (DDR), and the function of BAL1 remains undefined. Herein, we describe a direct link between rapid and short-lived poly(ADP-ribose) (PAR) polymerase 1 (PARP1) activation and PARylation atDNAdamage sites, PAR-dependent recruitment of the BAL1 macrodomain-containing protein and its partner 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 delayedDNAdamage and enhances cellular viability independent of ATM, MDC1, and RNF8. These data establish that BAL1 and BBAP are bona fide members of aDNAdamage response pathway and are directly associated with PARP1 activation, BRCA1 recruitment, and dou- ble-strand break repair.