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

Daniela Georgieva, Ning Wang, Angelo Taglialatela, Stepan Jerabek, Colleen R. Reczek, Pei Xin Lim, Julie Sung, Qian Du, Michiko Horiguchi, Maria Jasin, Alberto Ciccia, Richard Baer, Dieter Egli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number114006
JournalCell reports
Volume43
Issue number4
DOIs
StatePublished - Apr 23 2024

Keywords

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

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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