CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle
Open accessAbstract
The repair of DNA double-strand breaks (DSBs) is tightly regulated during the cell cycle. In G1 phase, the absence of a sister chromatid means that repair of DSBs occurs through non-homologous end-joining or microhomology-mediated end-joining (MMEJ). These pathways often involve loss of DNA sequences at the break site and are therefore error-prone. In late S and G2 phases, even though DNA end-joining pathways remain functional, there is an increase in repair of DSBs by homologous recombination, which is mostly error-free. Consequently, the relative contribution of these different pathways to DSB repair in the cell cycle has a large influence on the maintenance of genetic integrity. It has remained unknown how DSBs are directed for repair by different, potentially competing, repair pathways. Here we identify a role for CtIP (also known as RBBP8) in this process in the avian B-cell line DT40. We establish that CtIP is required not only for repair of DSBs by homologous recombination in S/G2 phase but also for MMEJ in G1. The function of CtIP in homologous recombination, but not MMEJ, is dependent on the phosphorylation of serine residue 327 and recruitment of BRCA1. Cells expressing CtIP protein that cannot be phosphorylated at serine 327 are specifically defective in homologous recombination and have a decreased level of single-stranded DNA after DNA damage, whereas MMEJ remains unaffected. Our data support a model in which phosphorylation of serine 327 of CtIP as cells enter S phase and the recruitment of BRCA1 functions as a molecular switch to shift the balance of DSB repair from error-prone DNA end-joining to error-free homologous recombination.
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MMEJ functions when DNA bases contain a small amount of sequence homology (microhomology), which can be either terminal on broken ends or embedded within the broken piece of DNA.
“This functions when DNA bases contain a small amount of sequence homology (microhomology), which can be either terminal on broken ends or embedded within the broken piece of DNA.”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [70]
A recently discovered sub-pathway called microhomology mediated end joining (MMEJ) operates in conjunction with both NHEJ and HR and utilizes CtIP.
“It is important to note that a recently discovered sub-pathway operates in conjunction with both NHEJ and HR called microhomology mediated end joining (MMEJ) utilizing a protein called CtIP [70,71].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [70]
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- Authors
- Yun, M. H., & Hiom, K.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Hiom, Kevin
- Venue
- Nature
- Published
- 2009-04-08
- Volume
- 459
- Issue
- 7245
- Pages
- 460-463
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2857324
- OpenAlex
- W2026959390
- Cited by
- 556
- References
- 21
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 27 · 2023: 20 · 2022: 21 · 2021: 39 · 2020: 27 · 2019: 19 · 2018: 32 · 2017: 32 · 2016: 26 · 2015: 44 · 2014: 46 · 2013: 45 · 2012: 42
- FWCI
- 20.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- CtIP, BRCA1, DNA double-strand break repair, homologous recombination, non-homologous end joining, microhomology-mediated end joining, DNA end resection, RBBP8, G1 phase, S/G2 phase, DT40 B cells
- MeSH terms
- Animals, B-Lymphocytes, Carrier Proteins, Cell Cycle, Cell Line, Chickens, Cisplatin, DNA Repair, Endodeoxyribonucleases, Humans, Nuclear Proteins, Phosphorylation, Phosphoserine, Recombination, Genetic, X-Rays, G1 Phase, G2 Phase, S Phase, BRCA1 Protein, Avian Proteins, DNA Breaks, Double-Stranded
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