The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
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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In the citing paper
“ATR in complex with its nuclear binding partner ATR-interacting protein (ATRIP) binds to this RPA-coated ssDNA via an ATRIP-RPA interaction. ATRIP also serves to activate the checkpoint kinase activity of ATR 4, 27–30.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [29]
In the citing paper
“In addition, during S phase, replication forks encounter the CPD and 6-4PP lesions that provoke stalling of the replication forks at the single-strand breaks (SSBs).”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [18]
In the citing paper
“These breaks are processed to long ssDNA, where RPA binds and initiates the recruitment of a complex array of DNA damage response (DDR) proteins, including ATRIP-ATR complex, TopBP1, MRE11, Rad50, Rad17, and 9-1-1 complex [17–19].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [18]
In the citing paper
“ATR is the primary sensor of single-stranded (ssDNA) breaks (SSB) caused by UV damage and replication stress.”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [16]
In the citing paper
“It has been shown that DNA damage and replication intermediates increase the unwinding of DNA, leading to the accumulation of RPA-coated ss-DNA, which recruits ATR [15, 16].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [16]
In the citing paper
“It has been shown that in response to UV irradiation, RPA-coated single-stranded DNA (ssDNA) recruits ATR to the UV damage site [15, 16].”
From NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (2013) · cites this paper as [16]
In the citing paper
“Given the variety of DNA lesions the cell has to deal with, it was hypothesized that the first responders, among checkpoint factors, had to be recruited to a common DNA intermediate, which was later identified as long regions of ssDNA covered by RPA [44].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [44]
In the citing paper
“While ATRIP and Ddc2 directly bind RPA-covered ssDNA [44], loading of the 9-1-1 complex requires the activity of an RFC-like complex, that places it at the junction between dsDNA and 5′ ssDNA [45].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [44]
In the citing paper
“ATR-interacting protein ATRIP is recruited to ssDNA via direct interaction between RPA and ATRIP, thereby recruiting ATR to RPA-ssDNA [100, 101].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [100]
Citations
Cites
The DNA damage response: putting checkpoints in perspective
Zhou, B.-B. S., & Elledge, S. J. (2000) · Nature · doi:10.1038/35044005 · Cited by 3,213
Self-citationCell cycle checkpoint signaling through the ATM and ATR kinases
Abraham, R. T. (2001) · Genes & Development · doi:10.1101/gad.914401 · Cited by 1,966
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Self-citationWold, M. S. (1997) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.66.1.61 · Cited by 1,445
ATR and ATRIP: Partners in Checkpoint Signaling
Cortez, D., Guntuku, S., Qin, J., & Elledge, S. J. (2001) · Science · doi:10.1126/science.1065521 · Cited by 985
Self-citationFork Reversal and ssDNA Accumulation at Stalled Replication Forks Owing to Checkpoint Defects
Sogo, J. M., Lopes, M., & Foiani, M. (2002) · Science · doi:10.1126/science.1074023 · Cited by 824
Loss of a yeast telomere: Arrest, recovery, and chromosome loss
Sandell, L. J. (1993) · Cell · doi:10.1016/0092-8674(93)90493-a · Cited by 792
Recombinant replication protein A: expression, complex formation, and functional characterization
Henricksen, L. A., Umbricht, C. B., & Wold, M. S. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)78100-9 · Cited by 597
Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress
Tibbetts, R. S., Cortez, D., Brumbaugh, K. M., Scully, R., Livingston, D., Elledge, S. J., & Abraham, R. T. (2000) · Genes & Development · doi:10.1101/gad.851000 · Cited by 512
Self-citation
Cited by
Sorted by citations
The DNA Damage Response: Making It Safe to Play with Knives
Ciccia, A., & Elledge, S. J. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.019 · Cited by 4,368
Self-citationMolecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073723 · Cited by 3,317
Cell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836
DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
Bartkova, J., Hořejší, Z., Koed, K., Krämer, A., Tort, F., Zieger, K., Guldberg, P., Sehested, M., Nesland, J. M., Lukas, C., et al. (2005) · Nature · doi:10.1038/nature03482 · Cited by 2,688
Causes and consequences of replication stress
Zeman, M. K., & Cimprich, K. A. (2014) · Nature Cell Biology · doi:10.1038/ncb2897 · Cited by 2,079
Metadata
- 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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