Cited by 874DNA Repair MechanismsEffects of Radiation ExposureCancer-related Molecular Pathways

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MDC1 is a mediator of the mammalian DNA damage checkpoint

Stewart, Grant S., Wang, Bin, Bignell, Colin R., Taylor, A. Malcolm R., Elledge, Stephen J.·2003·Nature

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Abstract

To counteract the continuous exposure of cells to agents that damage DNA, cells have evolved complex regulatory networks called checkpoints to sense DNA damage and coordinate DNA replication, cell-cycle arrest and DNA repair. It has recently been shown that the histone H2A variant H2AX specifically controls the recruitment of DNA repair proteins to the sites of DNA damage. Here we identify a novel BRCA1 carboxy-terminal (BRCT) and forkhead-associated (FHA) domain-containing protein, MDC1 (mediator of DNA damage checkpoint protein 1), which works with H2AX to promote recruitment of repair proteins to the sites of DNA breaks and which, in addition, controls damage-induced cell-cycle arrest checkpoints. MDC1 forms foci that co-localize extensively with gamma-H2AX foci within minutes after exposure to ionizing radiation. H2AX is required for MDC1 foci formation, and MDC1 forms complexes with phosphorylated H2AX. Furthermore, this interaction is phosphorylation dependent as peptides containing the phosphorylated site on H2AX bind MDC1 in a phosphorylation-dependent manner. We have shown by using small interfering RNA (siRNA) that cells lacking MDC1 are sensitive to ionizing radiation, and that MDC1 controls the formation of damage-induced 53BP1, BRCA1 and MRN foci, in part by promoting efficient H2AX phosphorylation. In addition, cells lacking MDC1 also fail to activate the intra-S phase and G2/M phase cell-cycle checkpoints properly after exposure to ionizing radiation, which was associated with an inability to regulate Chk1 properly. These results highlight a crucial role for MDC1 in mediating transduction of the DNA damage signal.

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Authors: Stewart, G. S., Wang, B., Bignell, C. R., Taylor, A. M. R., & Elledge, S. J.
Affiliations: Baylor College of Medicine (US)
University of Birmingham (GB)
Howard Hughes Medical Institute (US)
Corresponding author: Elledge, Stephen J.
ORCID: Stewart, Grant S.
Wang, Bin
Taylor, A. Malcolm R.
Elledge, Stephen J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2003-02
Volume: 421
Issue: 6926
Pages: 961-966
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature01446
OpenAlex: W1980017984
Cited by: 874
References: 30
Citations by year: 2026: 9 · 2025: 14 · 2024: 20 · 2023: 22 · 2022: 38 · 2021: 28 · 2020: 25 · 2019: 32 · 2018: 32 · 2017: 33 · 2016: 31 · 2015: 39 · 2014: 38 · 2013: 45 · 2012: 44
FWCI: 19.88
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders: Howard Hughes Medical Institute
European Molecular Biology Organization
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: MDC1, DNA damage checkpoint, H2AX phosphorylation, γH2AX foci, BRCA1, BRCT domain, FHA domain, radiosensitivity, 53BP1 foci, MRN complex, Chk1, cell cycle arrest, DNA double-strand breaks, signal transduction
MeSH terms: Tumor Suppressor p53-Binding Protein 1, Checkpoint Kinase 1, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, DNA Damage, DNA-Binding Proteins, Gamma Rays, Histones, Humans, Molecular Sequence Data, Mutation, Nuclear Proteins, Phosphoproteins, Phosphorylation, Protein Binding, Protein Kinases, Tumor Cells, Cultured, Signal Transduction, Trans-Activators, Protein Serine-Threonine Kinases, Cell Cycle Proteins, BRCA1 Protein, RNA, Small Interfering, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Mice, Checkpoint Kinase 2

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MDC1 is a mediator of the mammalian DNA damage checkpoint

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