Official websites use. Share sensitive information only on official, secure websites. In this review, Mirman et al. 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 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. Every eukaryotic cell contends with a staggering variety and quantity of threats to its DNA, with insults generating double-strand breaks DSBs representing perhaps the most toxic events.
Although 53BP1 was discovered and named based on its interaction with p53 Iwabuchi et al. Chief among these effector proteins are those that affect the formation of single-strand DNA ssDNA at breaks, which is an important step in repair of physiological and pathological DSBs Symington and Gautier ; Hustedt and Durocher The two predominant DSB repair pathways in mammalian cells.
This pathway is active throughout the cell cycle and the result is accurate repair or small insertions or deletions indels. Single-strand annealing SSA , resulting in deletions, can also occur if excessive resection exposes regions of homology. If the second end is not captured, the extended overhang can anneal to sequences at the second end after resection in a process called synthesis-dependent strand annealing SDSA Fig. It is at this node that 53BP1 has been implicated.
Domain structure and function of 53BP1. A Schematic of human 53BP1. X indicates no requirement; a check mark indicates a requirement. Darker check marks indicate greater dependency. ATM signaling initiates a cascade of chromatin phosphorylation and ubiquitination events, leading to recognition of chromatin by the 53BP1 FFR. This feature could explain the 53BP1-mediated synapsis of distal DSBs, which occurs in certain contexts [e. The contribution of these factors varies depending on the context of the DSBs being repaired as discussed in detail below.
