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

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

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.

Integrity signals

Registry

Crossref · 10.1038/nature01446

Cites

30 of 30 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • MDC1 is a binding partner of the MRN nuclease complex and functions in the initial detection and signaling of DSBs.

    “MDC1 is a binding partner of the MRN nuclease complex (Goldberg et al., 2003) and functions in the initial detection and signaling of DSBs (Stewart et al., 2003).”

    From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Stewart et al., 2003

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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.
Venue
Nature
Published
2003-02
Volume
421
Issue
6926
Pages
961-966
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
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
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

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 ›

Are you an author, or do you see a problem with this page? Request a review