BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks

Cell Rep. 2024 Apr 23;43(4):114006. doi: 10.1016/j.celrep.2024.114006. Epub 2024 Mar 30.


Reprogramming to pluripotency is associated with DNA damage and requires the functions of the BRCA1 tumor suppressor. Here, we leverage separation-of-function mutations in BRCA1/2 as well as the physical and/or genetic interactions between BRCA1 and its associated repair proteins to ascertain the relevance of homology-directed repair (HDR), stalled fork protection (SFP), and replication gap suppression (RGS) in somatic cell reprogramming. Surprisingly, loss of SFP and RGS is inconsequential for the transition to pluripotency. In contrast, cells deficient in HDR, but proficient in SFP and RGS, reprogram with reduced efficiency. Conversely, the restoration of HDR function through inactivation of 53bp1 rescues reprogramming in Brca1-deficient cells, and 53bp1 loss leads to elevated HDR and enhanced reprogramming in mouse and human cells. These results demonstrate that somatic cell reprogramming is especially dependent on repair of replication-associated double-strand breaks (DSBs) by the HDR activity of BRCA1 and BRCA2 and can be improved in the absence of 53BP1.

Keywords: BRCA1; BRCA2; CP: Molecular biology; double-strand break; pluripotency; replication gap suppression; replication stress; somatic cell reprogramming; stalled replication fork.

Publication types

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

MeSH terms

  • Animals
  • BRCA1 Protein* / genetics
  • BRCA1 Protein* / metabolism
  • Cellular Reprogramming*
  • DNA Breaks, Double-Stranded*
  • DNA Repair*
  • DNA Replication
  • Humans
  • Mice
  • Recombinational DNA Repair
  • Tumor Suppressor p53-Binding Protein 1* / genetics
  • Tumor Suppressor p53-Binding Protein 1* / metabolism


  • BRCA1 Protein
  • BRCA1 protein, human
  • Brca1 protein, mouse
  • TP53BP1 protein, human
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1