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BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated double-strand breaks
D. Georgieva, N. Wang, A. Taglialatela, S. Jerabek, CR. Reczek, PX. Lim, J. Sung, Q. Du, M. Horiguchi, M. Jasin, A. Ciccia, R. Baer, D. Egli
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural
Grant support
R35 CA253174
NCI NIH HHS - United States
NLK
Cell Press Free Archives
from 2012
Directory of Open Access Journals
from 2012
Free Medical Journals
from 2012
Freely Accessible Science Journals
from 2012-01-26
Open Access Digital Library
from 2012-01-26
Open Access Digital Library
from 2012-01-01
- MeSH
- Tumor Suppressor p53-Binding Protein 1 * metabolism genetics MeSH
- DNA Breaks, Double-Stranded * MeSH
- Humans MeSH
- Mice MeSH
- DNA Repair * MeSH
- Cellular Reprogramming * MeSH
- BRCA1 Protein * metabolism genetics MeSH
- Recombinational DNA Repair MeSH
- DNA Replication MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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
Developmental Biology Program Memorial Sloan Kettering Cancer Center New York NY 10065 USA
References provided by Crossref.org
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- $a 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.
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