Cited by 288DNA Repair MechanismsGenetic factors in colorectal cancerDNA and Nucleic Acid Chemistry

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ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts

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Yoshioka, Ken-ichi, Yoshioka, Yoshiko, Hsieh, Peggy·2006·Molecular Cell

DOI 10.1016/j.molcel.2006.04.023PMC PMC2423943

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Abstract

S(N)1-type alkylating agents that produce cytotoxic O(6)-methyl-G (O(6)-meG) DNA adducts induce cell cycle arrest and apoptosis in a manner requiring the DNA mismatch repair (MMR) proteins MutSalpha and MutLalpha. Here, we show that checkpoint signaling in response to DNA methylation occurs during S phase and requires DNA replication that gives rise to O(6)-meG/T mispairs. DNA binding studies reveal that MutSalpha specifically recognizes O(6)-meG/T mispairs, but not O(6)-meG/C. In an in vitro assay, ATR-ATRIP, but not RPA, is preferentially recruited to O(6)-meG/T mismatches in a MutSalpha- and MutLalpha-dependent manner. Furthermore, ATR kinase is activated to phosphorylate Chk1 in the presence of O(6)-meG/T mispairs and MMR proteins. These results suggest that MMR proteins can act as direct sensors of methylation damage and help recruit ATR-ATRIP to sites of cytotoxic O(6)-meG adducts to initiate ATR checkpoint signaling.

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Self-citation

Authors: Yoshioka, K.-I., Yoshioka, Y., & Hsieh, P.
Affiliations: National Institutes of Health (US)
Corresponding author: Hsieh, Peggy
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2006-05
Volume: 22
Issue: 4
Pages: 501-510
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2006.04.023
PMC: PMC2423943
OpenAlex: W2163529853
Cited by: 288
References: 49
Citations by year: 2026: 7 · 2025: 4 · 2024: 12 · 2023: 4 · 2022: 14 · 2021: 15 · 2020: 8 · 2019: 9 · 2018: 6 · 2017: 7 · 2016: 13 · 2015: 15 · 2014: 9 · 2013: 15 · 2012: 13
FWCI: 11.68
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 2634 d)
Locations: Molecular Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Massachusetts General Hospital
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (Z01DK052029)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords: MutSα, MutLα, DNA mismatch repair, DNA replication checkpoint, S phase, Chk1 phosphorylation, DNA damage recognition
MeSH terms: Animals, Base Sequence, Carrier Proteins, Cell Line, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Enzyme Activation, Exodeoxyribonucleases, Guanine, HeLa Cells, Humans, Nuclear Proteins, Phosphoproteins, Signal Transduction, S Phase, Protein Serine-Threonine Kinases, DNA Adducts, Cell Cycle Proteins, Base Pair Mismatch, Adaptor Proteins, Signal Transducing, Mice, MutS DNA Mismatch-Binding Protein, Ataxia Telangiectasia Mutated Proteins

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ATR Kinase Activation Mediated by MutSα and MutLα in Response to Cytotoxic O6-Methylguanine Adducts

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