BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks Journal Article
| Authors: | Georgieva, D.; Wang, N.; Taglialatela, A.; Jerabek, S.; Reczek, C. R.; Lim, P. X.; Sung, J.; Du, Q.; Horiguchi, M.; Jasin, M.; Ciccia, A.; Baer, R.; Egli, D. |
| Article Title: | BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks |
| 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. © 2024 The Author(s) |
| Keywords: | signal transduction; controlled study; missense mutation; nonhuman; flow cytometry; cell proliferation; phenotype; dna damage; homologous recombination; cell division; dna repair; somatic cell; apoptosis; embryo; cell differentiation; tumor suppressor gene; alkaline phosphatase; genetic transfection; immunocytochemistry; gene interaction; rat; cancer stem cell; double stranded dna break; upregulation; pluripotent stem cell; dna replication origin; dna extraction; brca1; atr protein; brca2; rad51 protein; nuclear reprogramming; immunofluorescence microscopy; colony formation; double-strand break; pluripotency; replication stress; homology directed repair; somatic cell reprogramming; induced pluripotent stem cell; stalled replication fork; article; tumor suppressor p53 binding protein 1; cp: molecular biology; apoptosis assay; replication gap suppression |
| Journal Title: | Cell Reports |
| Volume: | 43 |
| Issue: | 4 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2024-04-23 |
| Start Page: | 114006 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2024.114006 |
| PUBMED: | 38554279 |
| PROVIDER: | scopus |
| PMCID: | PMC11272184 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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