DNA Damage Sensing by the ATM and ATR Kinases
Open accessAbstract
In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrated by the ATM and ATR kinases is the central regulator of this network in response to DNA damage. Both ATM and ATR are activated by DNA damage and DNA replication stress, but their DNA-damage specificities are distinct and their functions are not redundant. Furthermore, ATM and ATR often work together to signal DNA damage and regulate downstream processes. Here, we will discuss the recent findings and current models of how ATM and ATR sense DNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR.
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Although both ATM and ATR are activated upon DNA damage, they have distinct DNA specificities; ATM is activated predominantly by DSBs whereas ATR responds to a broad spectrum of DNA damage including genotoxic stress caused by DNA replication stress initiated by oncogenes.
“Although both ATM and ATR are activated upon DNA damage, they have distinct DNA specificities; ATM gets activated predominantly by DSBs whereas ATR in addition to double strand breaks responds to a broad spectrum of DNA damage such as genotoxic stress caused by DNA replication stress initiated by oncogenes (Maréchal and Zou, 2013).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Maréchal and Zou, 2013
ATR is the main regulator of nucleotide excision repair because it detects replication and transcription stress caused by UV-induced and other bulky DNA adducts.
“Although it functions in multiple DDR processes 21 ATR is the primary regulator of the nucleotide excision repair pathway due to its ability to detect the replicative and transcriptional stresses caused by UV-induced damage and other bulky DNA adducts resulting from chemical toxins and some chemotherapeutic agents 22–25.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [25]
DNA damage-induced phosphorylation of p53, Mdm2, Mdm4, and DAXX by ATM and Chk2 contributes to the switch.
“A contributor to this switch is the DNA damage-induced phosphorylation of p53, Mdm2, Mdm4, and DAXX by the Ataxia telangiectasia mutated (ATM) kinase and its downstream effector kinase, Chk2 (Cheng and Chen, 2010; Maréchal and Zou, 2013).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Maréchal and Zou, 2013
DNA damage response pathways are conserved surveillance mechanisms that coordinate DNA repair, cell cycle progression, transcription, apoptosis, and senescence.
“To maintain genome stability, the DDR pathways are conserved surveillance mechanisms coordinating DNA repair, cell cycle progression, transcription, apoptosis, and senescence [19, 39–41].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [40]
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“A contributor to this switch is the DNA damage-induced phosphorylation of p53, Mdm2, Mdm4, and DAXX by the Ataxia telangiectasia mutated (ATM) kinase and its downstream effector kinase, Chk2 (Cheng and Chen, 2010; Maréchal and Zou, 2013).”
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- Authors
- Marechal, A., & Zou, L.
- Affiliations
- Harvard University (US)
- ORCID
- Zou, L.
- Venue
- Cold Spring Harbor Perspectives in Biology
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2013-09-01
- Volume
- 5
- Issue
- 9
- Pages
- a012716-a012716
- ISSN
- 1943-0264 (ISSN-L)
- PMC
- PMC3753707
- OpenAlex
- W2153466677
- Cited by
- 1,514
- References
- 156
- Citations by year
- 2026: 92 · 2025: 134 · 2024: 158 · 2023: 158 · 2022: 162 · 2021: 193 · 2020: 156 · 2019: 136 · 2018: 118 · 2017: 95 · 2016: 55 · 2015: 29 · 2014: 22 · 2013: 2 · 2012: 2
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cold Spring Harbor Perspectives in Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health
- Fonds de Recherche du Québec - Santé
- National Institute of General Medical Sciences (R01GM076388, GM076388)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- ATM kinase, ATR kinase, DNA damage response, DNA damage recognition, replication stress, genome stability, kinase activation, DNA repair, cell cycle regulation
- MeSH terms
- Chromatin, DNA Damage, Models, Molecular, Signal Transduction, Receptor Cross-Talk, Ataxia Telangiectasia Mutated Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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