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.

Columbia University Stem Cell Initiative New York NY 10032 USA; Department of Genetics and Development Herbert Irving Comprehensive Cancer Center Columbia University Irving Medical Center New York NY 10032 USA

Department of Pathology and Cell Biology Institute for Cancer Genetics Columbia University Irving Medical Center New York NY 10032 USA

Department of Pediatrics and Naomi Berrie Diabetes Center Columbia University Irving Medical Center New York NY 10032 USA

Department of Pediatrics and Naomi Berrie Diabetes Center Columbia University Irving Medical Center New York NY 10032 USA; Columbia University Stem Cell Initiative New York NY 10032 USA

Department of Pediatrics and Naomi Berrie Diabetes Center Columbia University Irving Medical Center New York NY 10032 USA; Columbia University Stem Cell Initiative New York NY 10032 USA; Department of Obstetrics and Gynecology Columbia University Irving Medical Center New York NY 10032 USA

Department of Pediatrics and Naomi Berrie Diabetes Center Columbia University Irving Medical Center New York NY 10032 USA; Columbia University Stem Cell Initiative New York NY 10032 USA; Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo namesti 542 2 160 00 Praha 6 Czech Republic

Developmental Biology Program Memorial Sloan Kettering Cancer Center New York NY 10065 USA

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