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BRCA1 and 53BP1 regulate reprogramming efficiency by mediating DNA repair pathway choice at replication-associated
Daniela Georgieva1, Ning Wang1, Angelo Taglialatela2
1Department 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.
Cell Reports
|March 30, 2024
Summary
Somatic cell reprogramming relies on BRCA1/2 for DNA repair via homology-directed repair (HDR). Enhancing HDR by removing 53BP1 improves reprogramming efficiency in mouse and human cells.
Area of Science:
- Cell biology
- Molecular genetics
- Cancer research
Background:
- Somatic cell reprogramming to pluripotency involves DNA damage.
- The BRCA1 tumor suppressor is crucial for this process.
- Specific DNA repair pathways like homology-directed repair (HDR) are implicated.
Purpose of the Study:
- To investigate the roles of HDR, stalled fork protection (SFP), and replication gap suppression (RGS) in somatic cell reprogramming.
- To understand the specific functions of BRCA1/2 in these pathways during reprogramming.
Main Methods:
- Utilizing separation-of-function mutations in BRCA1/2.
- Analyzing physical and genetic interactions between BRCA1 and repair proteins.
- Assessing reprogramming efficiency in cells with deficiencies or alterations in HDR, SFP, and RGS pathways.
Main Results:
- Loss of SFP and RGS functions did not impact pluripotency transition.
- Deficiency in HDR, but not SFP/RGS, reduced reprogramming efficiency.
- Restoring HDR by inactivating 53BP1 rescued reprogramming in BRCA1-deficient cells.
- 53BP1 loss enhanced HDR and reprogramming in both mouse and human cells.
Conclusions:
- Somatic cell reprogramming is highly dependent on BRCA1/2-mediated HDR for repairing replication-associated double-strand breaks (DSBs).
- The 53BP1 protein negatively regulates HDR during reprogramming.
- Inhibiting 53BP1 can improve somatic cell reprogramming efficiency.
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