CtIP Links DNA Double-Strand Break Sensing to Resection
Open accessAbstract
In response to DNA double-strand breaks (DSBs), cells sense the DNA lesions and then activate the protein kinase ATM. Subsequent DSB resection produces RPA-coated ssDNA that is essential for activation of the DNA damage checkpoint and DNA repair by homologous recombination (HR). However, the biochemical mechanism underlying the transition from DSB sensing to resection remains unclear. Using Xenopus egg extracts and human cells, we show that the tumor suppressor protein CtIP plays a critical role in this transition. We find that CtIP translocates to DSBs, a process dependent on the DSB sensor complex Mre11-Rad50-NBS1, the kinase activity of ATM, and a direct DNA-binding motif in CtIP, and then promotes DSB resection. Thus, CtIP facilitates the transition from DSB sensing to processing: it does so by binding to the DNA at DSBs after DSB sensing and ATM activation and then promoting DNA resection, leading to checkpoint activation and HR.
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Long single-stranded DNA can be generated by uncoupling MCM helicase and DNA polymerase during replication stress, by CtIP-mediated double-strand break end resection, by Exo1-mediated processing of nucleotide excision repair intermediates after UV, and by APE2-mediated single-strand break end resection in oxidative stress.
“A long stretch of ssDNA can be generated through the functional uncoupling of minichromosome maintenance (MCM) helicase and DNA polymerase in DNA replication stress, the DSB end resection by DNA exonuclease such as CtIP in DSB response, the Exo1-mediated processing of NER intermediates after UV radiation, and the SSB end resection by AP endonuclease 2 (APE2) in oxidative stress [86, 97–99]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [98]
End processing of double-strand breaks in homologous recombination contributes to DDR pathways.
“DSB end processing in HR also contributes to DDR pathways.”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [98]
CtIP is required for double-strand break end resection, recruitment of RPA and ATR to double-strand breaks, and subsequent ATR activation.
“CtIP is required for DSB end resection, the recruitment of RPA and ATR to DSBs, and subsequent ATR activation [98, 220]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [98]
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 [71]
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 [71]
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- Authors
- You, Z., Shi, L. Z., Zhu, Q., Wu, P., Zhang, Y.-W., Basilio, A., Tonnu, N., Verma, I. M., Berns, M. W., & Hunter, T.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Washington University in St. Louis (US)
- University of California, Irvine (US)
- Corresponding author
- You, Zhongsheng
- Hunter, Tony
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 36
- Issue
- 6
- Pages
- 954-969
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2807415
- OpenAlex
- W2021870890
- Cited by
- 231
- References
- 52
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 13 · 2021: 9 · 2020: 15 · 2019: 10 · 2018: 9 · 2017: 18 · 2016: 13 · 2015: 17 · 2014: 25 · 2013: 20 · 2012: 26
- FWCI
- 8.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA 14195, R00CA126173, R01CA080100, CA 80100, P30CA014195)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- CtIP, DNA double-strand breaks, ATM kinase, Mre11-Rad50-Nbs1 complex, homologous recombination, DNA damage checkpoint, DNA-binding motifs, tumor suppressor proteins, DNA repair
- MeSH terms
- Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, DNA Repair, DNA-Binding Proteins, Endodeoxyribonucleases, Enzyme Activation, Humans, Molecular Sequence Data, Nuclear Proteins, Oocytes, Recombinant Fusion Proteins, Recombination, Genetic, Xenopus laevis, Sequence Alignment, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins
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