53BP1 regulates heterochromatin through liquid phase separation

Nat Commun. 2022 Jan 18;13(1):360. doi: 10.1038/s41467-022-28019-y.


Human 53BP1 is primarily known as a key player in regulating DNA double strand break (DSB) repair choice; however, its involvement in other biological process is less well understood. Here, we report a previously uncharacterized function of 53BP1 at heterochromatin, where it undergoes liquid-liquid phase separation (LLPS) with the heterochromatin protein HP1α in a mutually dependent manner. Deletion of 53BP1 results in a reduction in heterochromatin centers and the de-repression of heterochromatic tandem repetitive DNA. We identify domains and residues of 53BP1 required for its LLPS, which overlap with, but are distinct from, those involved in DSB repair. Further, 53BP1 mutants deficient in DSB repair, but proficient in LLPS, rescue heterochromatin de-repression and protect cells from stress-induced DNA damage and senescence. Our study suggests that in addition to DSB repair modulation, 53BP1 contributes to the maintenance of heterochromatin integrity and genome stability through LLPS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromobox Protein Homolog 5 / metabolism
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Green Fluorescent Proteins / metabolism
  • Heterochromatin / metabolism*
  • Mice
  • Mice, Knockout
  • Mutation / genetics
  • Protein Domains
  • Stress, Physiological
  • Tumor Suppressor p53-Binding Protein 1 / chemistry
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*


  • Heterochromatin
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Chromobox Protein Homolog 5
  • Green Fluorescent Proteins