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More end resection is not merrier

Nature Structural & Molecular Biology volume 23, pages 699–701 (2016)Cite this article

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Unrestrained 53BP1 activity causes fusions of dysfunctional telomeres and embryonic lethality associated with misrepair of DNA double-strand breaks in BRCA1-deficient mice. However, the physiological role of 53BP1 remains unclear, because it presumably did not evolve to carry out these pathological functions. A new report proposes that 53BP1 activity prevents hyper-resection and thereby promotes error-free DNA repair while suppressing alternative mutagenic pathways.

The physiological function of 53BP1 during DSB repair has long been an enigma, given that it lacks enzymatic activity. Originally, 53BP1 was shown to promote long-range NHEJ during antigen-receptor rearrangements and in response to dysfunctional telomeres6,7,8,9. Beyond these NHEJ functions in G1, 53BP1 has been shown to antagonize the activity of the tumor suppressor and HDR protein BRCA1 in the S and G2 phases of the cell cycle. Dramatically, genetic ablation of 53BP1 rescues the embryonic lethal phenotype associated with BRCA1 deficiency10. Thus, in addition to its NHEJ-promoting role, unbridled 53BP1 activity causes lethality by blocking BRCA1-mediated HDR11,12. Further work has revealed that 53BP1 interacts with downstream effectors, RIF1 and PTIP, through phosphorylation-dependent protein interactions, and recruits them to damaged chromatin, where they block DSBs from resection by the nuclease CtIP13,14. This barrier to resection must be actively relieved by BRCA1 in S and G2 to enable repair by HDR; otherwise, unprocessed DSBs become potential substrates for nontemplate-driven ligation by error-prone NHEJ, thus resulting in the formation of highly aberrant toxic intermediates12. These studies have collectively contributed to the notion that 53BP1 is a general suppressor of end resection and HDR.

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Figure 1: 53BP1 restrains end resection, thereby promoting gene conversion and preventing single-strand annealing.
Figure 2: A model of pathway choice during DSB repair.

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Authors and Affiliations

  1. Dali Zong, Arnab Ray Chaudhuri and André Nussenzweig are at the Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.,

    Dali Zong, Arnab Ray Chaudhuri & André Nussenzweig

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  1. Dali Zong
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Correspondence to André Nussenzweig.

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Zong, D., Ray Chaudhuri, A. & Nussenzweig, A. More end resection is not merrier. Nat Struct Mol Biol 23, 699–701 (2016). https://doi.org/10.1038/nsmb.3274

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