Cited by 2,693DNA Repair MechanismsFungal and yeast genetics researchBacterial Genetics and Biotechnology

Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes

Zou, Lee, Elledge, Stephen J.·2003·Science

Abstract

The function of the ATR (ataxia-telangiectasia mutated– and Rad3-related)–ATRIP (ATR-interacting protein) protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Here, we show that replication protein A (RPA), a protein complex that associates with single-stranded DNA (ssDNA), is required for the recruitment of ATR to sites of DNA damage and for ATR-mediated Chk1 activation in human cells. In vitro, RPA stimulates the binding of ATRIP to ssDNA. The binding of ATRIP to RPA-coated ssDNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the Rad17 protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-strand DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11 , is defective for recruiting Ddc2 to ssDNA both in vivo and in vitro. Our data suggest that RPA-coated ssDNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling.

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Crossref · 10.1126/science.1083430

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Authors
Zou, L., & Elledge, S. J.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Elledge, Stephen J.
Venue
Science
Published
2003-06-06
Volume
300
Issue
5625
Pages
1542-1548
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2043895957
Cited by
2,693
References
37
Citations by year
2026: 64 · 2025: 65 · 2024: 114 · 2023: 98 · 2022: 112 · 2021: 136 · 2020: 111 · 2019: 116 · 2018: 106 · 2017: 114 · 2016: 130 · 2015: 139 · 2014: 117 · 2013: 144 · 2012: 121
FWCI
41.94
Type
journal article
Language
en
Open access
closed
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (GM-44664)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Keywords
replication protein A, single-stranded DNA, DNA damage recognition, DNA damage checkpoint, Chk1 activation, DNA double-strand breaks, replication stress
MeSH terms
Checkpoint Kinase 1, Cell Nucleus, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, DNA, Fungal, DNA, Single-Stranded, Enzyme Activation, Exodeoxyribonucleases, HeLa Cells, Humans, Mutation, Phosphoproteins, Phosphorylation, Protein Binding, Protein Kinases, Radiation, Ionizing, Recombination, Genetic, Saccharomyces cerevisiae, Transcription Factors, Transfection, Tumor Cells, Cultured, Ultraviolet Rays, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, Replication Protein A, Ataxia Telangiectasia Mutated Proteins

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