Chk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair
Open accessAbstract
The DNA damage response (DDR) has an essential function in maintaining genomic stability. Ataxia telangiectasia-mutated (ATM)-checkpoint kinase 2 (Chk2) and ATM- and Rad3-related (ATR)-Chk1, triggered, respectively, by DNA double-strand breaks and blocked replication forks, are two major DDRs processing structurally complicated DNA damage. In contrast, damage repaired by base excision repair (BER) is structurally simple, but whether, and how, the DDR is involved in repairing this damage is unclear. Here, we demonstrated that ATM-Chk2 was activated in the early response to oxidative and alkylation damage, known to be repaired by BER. Furthermore, Chk2 formed a complex with XRCC1, the BER scaffold protein, and phosphorylated XRCC1 in vivo and in vitro at Thr(284). A mutated XRCC1 lacking Thr(284) phosphorylation was linked to increased accumulation of unrepaired BER intermediate, reduced DNA repair capacity, and higher sensitivity to alkylation damage. In addition, a phosphorylation-mimic form of XRCC1 showed increased interaction with glycosylases, but not other BER proteins. Our results are consistent with the phosphorylation of XRCC1 by ATM-Chk2 facilitating recruitment of downstream BER proteins to the initial damage recognition/excision step to promote BER.
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Checkpoints actively stimulate repair processes and, in higher eukaryotes, trigger apoptosis when damage cannot be successfully dealt with.
“The checkpoints also actively stimulate the repair processes [1–9] and, in higher eukaryotes, trigger the apoptotic response, if damage cannot be dealt with successfully [10–12].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [7]
Chk2-dependent phosphorylation of XRCC1 at threonine 284 promotes XRCC1 recruitment to the initial lesion site recognized and excised by the DNA glycosylases MPG and UNG2.
“Chk2-dependent XRCC1 phosphorylation at Threonine 284 promotes the recruitment of XRCC1 to the initial lesion site recognized and excised by the DNA glycosylases MPG and UNG2 (Fig. 3) [168].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [168]
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References 50 · Cited by 104
- Authors
- Chou, W., Wang, H., Wong, F., Ding, S., Wu, P., Shieh, S., & Shen, C.
- Affiliations
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Kaohsiung Medical University (TW)
- National Yang Ming University (TW)
- Kang-Ning Junior College of Medical Care and Management (TW)
- China Medical University (TW)
- Corresponding author
- Shieh, Sheau‐Yann
- Shen, Chen‐Yang
- Venue
- The EMBO Journal
- Published
- 2008-10-30
- Volume
- 27
- Issue
- 23
- Pages
- 3140-3150
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC2599873
- OpenAlex
- W2041815718
- Cited by
- 104
- References
- 50
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 12 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 2 · 2017: 6 · 2016: 4 · 2015: 8 · 2014: 11 · 2013: 7 · 2012: 12
- FWCI
- 2.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Academia Sinica
- Institute of Biomedical Sciences, Academia Sinica
- 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
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- Chk2, XRCC1, ATM/Chk2 signaling, base excision repair, DNA damage response, oxidative DNA damage, alkylation damage, glycosylases, DNA repair intermediates, genome stability
- MeSH terms
- X-ray Repair Cross Complementing Protein 1, Alkylating Agents, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Phosphorylation, Protein Binding, Mutagenesis, Site-Directed, Oxidants, Protein Serine-Threonine Kinases, Cell Line, Tumor, Mutant Proteins, Checkpoint Kinase 2
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