53BP1 fosters fidelity of homology-directed DNA repair

Nat Struct Mol Biol. 2016 Aug;23(8):714-21. doi: 10.1038/nsmb.3251. Epub 2016 Jun 27.


Repair of DNA double-strand breaks (DSBs) in mammals is coordinated by the ubiquitin-dependent accumulation of 53BP1 at DSB-flanking chromatin. Owing to its ability to limit DNA-end processing, 53BP1 is thought to promote nonhomologous end-joining (NHEJ) and to suppress homology-directed repair (HDR). Here, we show that silencing 53BP1 or exhausting its capacity to bind damaged chromatin changes limited DSB resection to hyper-resection and results in a switch from error-free gene conversion by RAD51 to mutagenic single-strand annealing by RAD52. Thus, rather than suppressing HDR, 53BP1 fosters its fidelity. These findings illuminate causes and consequences of synthetic viability acquired through 53BP1 silencing in cells lacking the BRCA1 tumor suppressor. We show that such cells survive DSB assaults at the cost of increasing reliance on RAD52-mediated HDR, which may fuel genome instability. However, our findings suggest that when challenged by DSBs, BRCA1- and 53BP1-deficient cells may become hypersensitive to, and be eliminated by, RAD52 inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Humans
  • Protein Transport
  • Rad51 Recombinase / metabolism
  • Rad52 DNA Repair and Recombination Protein / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / physiology*


  • Chromatin
  • RAD52 protein, human
  • Rad52 DNA Repair and Recombination Protein
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • RAD51 protein, human
  • Rad51 Recombinase