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

The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.

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
DOI 10.1038/nature01446
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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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Crossref · 10.1038/nature01446

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Metadata

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
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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