53BP1: Keeping It under Control, Even at a Distance from DNA Damage

Abstract

Double-strand breaks (DSBs) are toxic lesions that can be generated by exposure to genotoxic agents or during physiological processes, such as during V(D)J recombination. The repair of these DSBs is crucial to prevent genomic instability and to maintain cellular homeostasis. Two main pathways participate in repairing DSBs, namely, non-homologous end joining (NHEJ) and homologous recombination (HR). The P53-binding protein 1 (53BP1) plays a pivotal role in the choice of DSB repair mechanism, promotes checkpoint activation and preserves genome stability upon DSBs. By preventing DSB end resection, 53BP1 promotes NHEJ over HR. Nonetheless, the balance between DSB repair pathways remains crucial, as unscheduled NHEJ or HR events at different phases of the cell cycle may lead to genomic instability. Therefore, the recruitment of 53BP1 to chromatin is tightly regulated and has been widely studied. However, less is known about the mechanism regulating 53BP1 recruitment at a distance from the DNA damage. The present review focuses on the mechanism of 53BP1 recruitment to damage and on recent studies describing novel mechanisms keeping 53BP1 at a distance from DSBs.

Protocol for automated multivariate quantitative-image-based cytometry analysis by fluorescence microscopy of asynchronous adherent cells

“…The recruitment of 53BP1 at DSB involves several reader domains interacting with specific histone marks. 22 , 28 53BP1 recruitment at damaged DNA involves direct interaction of the two 53BP1 BRCA-carboxyterminal (BRCT) repeats with locally induced γH2AX 29 , 30 and the recognition by the ubiquitin-dependent motif (UDR) of the DNA damage-induced ubiquitylated H2AK15 marks. 31 The TUDOR domain of 53BP1 can interact with the di-methylated histone H4 (H4K20me2) 32 , 33 that are unmasked in response to DNA damage 34 , 35 and the dilution of H4K20me2 with H4K20me0 during DNA replication reduces the recruitment 53BP1 to DBSs in the S/G2 phase.…”

Deciphering the phospho-signature induced by hepatitis B virus in primary human hepatocytes

“…Among these factors figured, notably, Ku70 (XRCC6), DDB2, Rad50, two sensors of DSBs (Kieffer and Lowndes, 2022), MDC1, and 53BP1 (Figure 4C). These proteins participate in a cascade of signaling events, including phosphorylation events, triggered by DNA damage, in particular by DSBs, that culminate with the recruitment of 53BP1 on chromatin, to form large foci that segregate damaged sites from the rest of the genome (Shibata and Jeggo, 2020;Rass et al, 2022)). During this process, phosphorylation of 53BP1 by the ATM kinase, among others, is critical for its recruitment to the sites of DNA damage (Jowsey et al, 2007).…”

CSB and SMARCAL1 compete for RPA32 at stalled forks and differentially control the fate of stalled forks in BRCA2-deficient cells

“…SMARCAL1 has been reported to promote nonhomologous end joining (NHEJ) ( 68 ), raising the possibility that downregulation of NHEJ resulting from loss of SMARCAL1 could channel DSBs towards repair by BIR in BRCA2-deficient cells. While depletion of SMARCAL1 does not affect NHEJ-mediated repair of I-SceI-induced DSBs (Figure 7E ), depletion of SMARCAL1 decreases HU-induced foci formation of 53BP1, a NHEJ-promoting factor ( 76 ), in S phase as marked by EdU (Figures 5D and 7B ). The latter supports the notion that SMARCAL1 promotes NHEJ to inhibit BIR-mediated restart of stalled forks in BRCA2-deficient cells.…”