ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage
Abstract
Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals.
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Activated ATR phosphorylates downstream mediators including Chk1, AKAP12, MK2, p53, ATRIP, and XPA.
“Activated ATR kinase phosphorylates many downstream mediators/effectors which include checkpoint kinase 1 (Chk1), A-kinase-anchoring protein 12 (AKAP12), p38/mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), the tumor suppressor protein p53, ATRIP and XPA 27, 31–33.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [33]
Effector kinases phosphorylate many targets, including cell cycle machinery and proteins important for replication and repair.
“Finally, effector kinases are responsible for the phosphorylation of a great number of targets, including cell cycle machinery factors and key proteins important for replication and repair [32,33].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [33]
CSB, the human orthologue of Rad26, was identified in a screen for putative ATM/ATR substrates, pointing to conservation of this regulatory mechanism.
“Notably, CSB (the human orthologue of Rad26) was identified in a screen for putative ATM/ATR substrates [33], pointing to a conservation of this regulatory mechanism through evolution.”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [33]
One of the CSB SQ/TQ motifs was recently identified as a target for ATM/ATR.
“one of these was recently identified as a target for ATM/ATR (32).”
From A Role for Checkpoint Kinase-Dependent Rad26 Phosphorylation in Transcription-Coupled DNA Repair in <i>Saccharomyces cerevisiae</i> (2010) · cites this paper as [32]
Systematic analyses of ATM/ATR substrates revealed ionizing radiation-induced phosphorylation of mismatch repair proteins MSH2, MSH3, and MSH6 and homologous recombination proteins Mre11, Rad50, MDC1, and Rad51.
“In addition, systematic analyses of ATM/ATR substrates have revealed several IR-induced phosphorylation in MMR (e.g., MSH2, MSH3, and MSH6) and HR (e.g., Mre11, Rad50, MDC1, and Rad51) proteins [83]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [83]
ATM phosphorylates H2AX and hundreds of other proteins upon double-strand DNA breaks.
“ATM is a DNA damage response kinase that phosphorylates H2AX and hundreds of other proteins upon double-strand DNA breaks.38”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [38]
The phosphorylation site ATM prefers is a serine or threonine followed by a glutamine (S/T-Q).
“The phosphorylation site ATM prefers is a serine or threonine followed by a glutamine (S/T-Q).38,39”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [38]
Phosphorylation of H2AX and S/T-Q sites occurs rapidly after DNA breaks.
“Phosphorylation of H2AX and S/T-Q sites, both of which are targets of ATM, occurs rapidly after DNA breaks.9,37,38”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [38]
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FUS is Phosphorylated by DNA-PK and Accumulates in the Cytoplasm after DNA Damage
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Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA‐PK
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- Authors
- Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., Hurov, K. E., Luo, J., Bakalarski, C. E., Zhao, Z., Solimini, N., Lerenthal, Y., Shiloh, Y., Gygi, S. P., & Elledge, S. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Ballif, Bryan A.
- Smogorzewska, Agata
- McDonald, E. Robert
- Hurov, Kristen E.
- Luo, Ji
- Gygi, Steven P.
- Elledge, Stephen J.
- ORCID
- Venue
- Science
- Published
- 2007-05-25
- Volume
- 316
- Issue
- 5828
- Pages
- 1160-1166
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2110817748
- Cited by
- 3,075
- References
- 31
- Citations by year
- 2026: 65 · 2025: 74 · 2024: 101 · 2023: 125 · 2022: 156 · 2021: 180 · 2020: 149 · 2019: 118 · 2018: 142 · 2017: 150 · 2016: 180 · 2015: 181 · 2014: 220 · 2013: 208 · 2012: 231
- FWCI
- 73.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (1U19A1067751)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- DNA damage response, ATM, ATR, protein phosphorylation, phosphorylation sites, protein networks, protein modules, signal transduction, protein kinases, proteomics
- MeSH terms
- Animals, Binding Sites, Cell Cycle, Cell Line, DNA Damage, DNA Repair, DNA Replication, DNA-Binding Proteins, Humans, Isotope Labeling, Phosphorylation, Substrate Specificity, Signal Transduction, Consensus Sequence, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Computational Biology, Proteome, Tumor Suppressor Proteins, RNA, Small Interfering, NIH 3T3 Cells, Immunoprecipitation, Mice, Ataxia Telangiectasia Mutated Proteins
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