53BP1: a DSB escort

Abstract

53BP1 is an enigmatic DNA damage response factor that gained prominence because it determines the efficacy of PARP1 inhibitory drugs (PARPi) in BRCA1-deficient cancers. Recent studies have elevated 53BP1 from its modest status of (yet another) DNA damage factor to master regulator of double-strand break (DSB) repair pathway choice. Our review of the literature suggests an alternative view. We propose that 53BP1 has evolved to avoid mutagenic repair outcomes and does so by controlling the processing of DNA ends and the dynamics of DSBs. The consequences of 53BP1 deficiency, such as diminished PARPi efficacy in BRCA1-deficient cells and altered repair of damaged telomeres, can be explained from this viewpoint. We further propose that some of the fidelity functions of 53BP1 coevolved with class switch recombination (CSR) in the immune system. We speculate that, rather than being deterministic in DSB repair pathway choice, 53BP1 functions as a DSB escort that guards against illegitimate and potentially tumorigenic recombination.

Under-Replicated DNA: The Byproduct of Large Genomes?

“…More than 25 years later, the biology of 53BP1 has taken a life of its own. 53BP1 is a large chromatin-binding protein that functions as a molecular scaffold, bridging interactions between damaged chromatin and several effector proteins implicated mainly in DNA lesion processing [ 99 , 101 , 102 ]. Its role in DSB repair has been studied in much detail.…”

“…The extent of 5’-3′ nucleolytic digestion of broken DNA ends determines which repair pathway is chosen to process these lesions: No or minimally processed DSB ends are repaired by non-homologous end joining (NHEJ), whereas resected DSB ends are repaired by homology-directed repair (HDR) [ 102 ]. 53BP1 is essential for this choice: it limits DNA resection at broken ends, and in some cases even reverses it, greatly increasing the use of NHEJ in certain contexts [ 101 , 103 ]. 53BP1 is not a core NHEJ factor, yet it is critical for both the execution of physiological NHEJ-driven events like immunoglobulin class switching and for the triggering of pathological ones, like the fusion of unprotected telomere ends or the chromosomal aberrations seen in cells deficient in BRCA1 [ 103 , 104 ].…”

Replicated chromatin curtails 53BP1 recruitment in BRCA1-proficient and -deficient cells

“…in G1/G0 cells and in unreplicated regions of the genome during S-phase progression), together with DNA damage-induced chromatin modifications that promote multivalent 53BP1 chromatin binding, provides a scaffold for efficient 53BP1 assembly around DNA break sites in the absence of a replicated template DNA required for HR repair. We therefore suggest that the effect of H4K20me2 dilution on 53BP1 assembly in nascent replicated chromatin functionally cooperates with the effect of H4K20me0-mediated BRCA1-BARD1 recruitment and the ensuing 53BP1 displacement, and that together they represent a dual switch to ensure that DSBs in unreplicated areas of the genome are protected from excessive DNA end resection and illegitimate recombination 28 and channeled towards NHEJ, while DSBs in replicated areas of the genome are released from the DNA end protection functions of 53BP1 and channeled towards resection and HR ( Figure 7). Accordingly, the mutual antagonism between 53BP1 and BRCA1-BARD1 may be seen as a bistable system, the robustness of which is achieved by cooperative effects resulting from high affinity 53BP1…”

ZEB1 is Required for NHEJ-Mediated DSB Repair in Euchromatin

“…53BP1 rapidly localizes to DSBs, via recognition of specific ubiquitinated and methylated histone marks, to promote NHEJ by nucleating the anti-resection complex shieldin (20)(21)(22)(23)(24)(25). 53BP1 is required for CSR, mid-range V[D]J recombination, and fusion of de-protected/dysfunctional telomeres (26). Depletion of 53BP1 radio-sensitizes normal as well as tumor cells in culture and in xenografts, dramatically increases the number and size of insertions and deletions (indels) at repair junctions, and increases chromosomal aberrations (27)(28)(29)(30)(31).…”