Cited by 1,514DNA Repair MechanismsCancer-related Molecular PathwaysGenomics and Chromatin Dynamics

DNA Damage Sensing by the ATM and ATR Kinases

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Marechal, A., Zou, L.·2013·Cold Spring Harbor Perspectives in Biology

Abstract

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).”
  • 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.”
  • 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].”

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Authors
Marechal, A., & Zou, L.
Affiliations
Harvard University (US)
ORCID
Zou, L.
Venue
Cold Spring Harbor Perspectives in Biology
Published
2013-09-01
Volume
5
Issue
9
Pages
a012716-a012716
ISSN
1943-0264 (ISSN-L)
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
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

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