MDC1 is required for the intra-S-phase DNA damage checkpoint
Abstract
MRE11, RAD50 and NBS1 form a highly conserved protein complex (the MRE11 complex) that is involved in the detection, signalling and repair of DNA damage. We identify MDC1 (KIAA0170/NFBD1), a protein that contains a forkhead-associated (FHA) domain and two BRCA1 carboxy-terminal (BRCT) domains, as a binding partner for the MRE11 complex. We show that, in response to ionizing radiation, MDC1 is hyperphosphorylated in an ATM-dependent manner, and rapidly relocalizes to nuclear foci that also contain the MRE11 complex, phosphorylated histone H2AX and 53BP1. Downregulation of MDC1 expression by small interfering RNA yields a radio-resistant DNA synthesis (RDS) phenotype and prevents ionizing radiation-induced focus formation by the MRE11 complex. However, downregulation of MDC1 does not abolish the ionizing radiation-induced phosphorylation of NBS1, CHK2 and SMC1, or the degradation of CDC25A. Furthermore, we show that overexpression of the MDC1 FHA domain interferes with focus formation by MDC1 itself and by the MRE11 complex, and induces an RDS phenotype. These findings reveal that MDC1-mediated focus formation by the MRE11 complex at sites of DNA damage is crucial for the efficient activation of the intra-S-phase checkpoint.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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 Goldberg et al., 2003
MDC1 is phosphorylated by ATM and relocalizes to damage sites containing MRN, γ-H2AX, and 53BP1, and it is indispensable for the ATM-dependent DNA damage checkpoint.
“With a forkhead-associated (FHA) domain and two BRCT domains, MDC1 is phosphorylated by ATM and relocalizes to damage sites that contain the MRN complex, γ-H2AX, and 53BP1, thereby playing an indispensable role in ATM-dependent DNA damage checkpoint [61].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [61]
Cites
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., et al. (1995) · Science · doi:10.1126/science.7792600 · Cited by 2,785 · see citing works
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J., & Lukas, J. (2001) · Nature · doi:10.1038/35071124 · Cited by 1,085 · see citing works
Self-citationThe MRE11 complex: at the crossroads of DNA repair and checkpoint signalling
D'Amours, D., & Jackson, S. P. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm805 · Cited by 874 · see citing works
Self-citationA superfamily of conserved domains in DNA damage‐ responsive cell cycle checkpoint proteins
Bork, P., Hofmann, K., Bucher, P., Neuwald, A. F., Altschul, S. F., & Koonin, E. V. (1997) · The FASEB Journal · doi:10.1096/fasebj.11.1.9034168 · Cited by 746 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Molecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073723 · Cited by 3,317 · see citing works
Cell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836 · see citing works
Self-citationA DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,855 · see citing works
Self-citationChk1 and Chk2 kinases in checkpoint control and cancer
Bartek, J., & Lukas, J. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00110-7 · Cited by 1,513 · see citing works
Self-citationLiving on a break: cellular senescence as a DNA-damage response
d'Adda di Fagagna, F. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2440 · Cited by 1,170 · see citing works
Requirement of the MRN complex for ATM activation by DNA damage
Uziel, T., Lerenthal, Y., Moyal, L., Andegeko, Y., Mittelman, L., & Shiloh, Y. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg541 · Cited by 1,075 · see citing works
DNA damage responses to oxidative stress
Barzilai, A., & Yamamoto, K.-I. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.002 · Cited by 796 · see citing works
XLF Interacts with the XRCC4-DNA Ligase IV Complex to Promote DNA Nonhomologous End-Joining
Ahnesorg, P., Smith, P., & Jackson, S. P. (2006) · Cell · doi:10.1016/j.cell.2005.12.031 · Cited by 794 · see citing works
Self-citationChecking on DNA damage in S phase
Bartek, J., Lukas, C., & Lukas, J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1493 · Cited by 758 · see citing works
Self-citationγH2AX and MDC1: Anchoring the DNA-damage-response machinery to broken chromosomes
Stucki, M., & Jackson, S. P. (2006) · DNA Repair · doi:10.1016/j.dnarep.2006.01.012 · Cited by 412 · see citing works
Self-citationWilliams, R. S., Williams, J. S., & Tainer, J. A. (2007) · Biochemistry and Cell Biology · doi:10.1139/o07-069 · Cited by 399 · see citing works
Mammalian cell cycle checkpoints: signalling pathways and their organization in space and time
Lukas, J., Lukas, C., & Bartek, J. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.006 · Cited by 381 · see citing works
Self-citationThompson, L. H. (2012) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2012.06.002 · Cited by 357 · see citing works
The cellular response to DNA double-strand breaks: defining the sensors and mediators
Petrini, J. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00170-3 · Cited by 339 · see citing works
Williams, R. S., Dodson, G. E., Limbo, O., Yamada, Y., Williams, J. S., Guenther, G., Classen, S., Glover, J. N. M., Iwasaki, H., Russell, P., et al. (2009) · Cell · doi:10.1016/j.cell.2009.07.033 · Cited by 322 · see citing works
Activation of the Cellular DNA Damage Response in the Absence of DNA Lesions
Soutoglou, E., & Misteli, T. (2008) · Science · doi:10.1126/science.1159051 · Cited by 299 · see citing works
The MRN complex: coordinating and mediating the response to broken chromosomes
van den Bosch, M., Bree, R. T., & Lowndes, N. F. (2003) · The EMBO Reports · doi:10.1038/sj.embor.embor925 · Cited by 289 · see citing works
Histone H2AX Phosphorylation as a Predictor of Radiosensitivity and Target for Radiotherapy
Taneja, N., Davis, M., Choy, J. S., Beckett, M. A., Singh, R., Kron, S. J., & Weichselbaum, R. R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310030200 · Cited by 281 · see citing works
Functional links between telomeres and proteins of the DNA-damage response
d'Adda di Fagagna, F., Teo, S.-H., & Jackson, S. P. (2004) · Genes & Development · doi:10.1101/gad.1214504 · Cited by 277 · see citing works
Self-citationStracker, T. H., Theunissen, J.-W. F., Morales, M., & Petrini, J. H. J. (2004) · DNA Repair · doi:10.1016/j.dnarep.2004.03.014 · Cited by 263 · see citing works
Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage
Yin, Y., Seifert, A., Chua, J. S., Maure, J.-F., Golebiowski, F., & Hay, R. T. (2012) · Genes & Development · doi:10.1101/gad.189274.112 · Cited by 237 · see citing works
Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains
Rodriguez, M., Yu, X., Chen, J., & Songyang, Z. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300407200 · Cited by 234 · see citing works
HP1α recruitment to DNA damage by p150CAF-1 promotes homologous recombination repair
Baldeyron, C., Soria, G., Roche, D., Cook, A. J. L., & Almouzni, G. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201101030 · Cited by 200 · see citing works
Structure of the BRCT Repeats of BRCA1 Bound to a BACH1 Phosphopeptide
Shiozaki, E. N., Gu, L., Yan, N., & Shi, Y. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00238-2 · Cited by 174 · see citing works
Matsumoto, M., Yaginuma, K., Igarashi, A., Imura, M., Hasegawa, M., Iwabuchi, K., Date, T., Mori, T., Ishizaki, K., Yamashita, K., et al. (2007) · Journal of Cell Science · doi:10.1242/jcs.03391 · Cited by 138 · see citing works
USP7 Is a Master Regulator of Genome Stability
Valles, G. J., Bezsonova, I., Woodgate, R., & Ashton, N. W. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00717 · Cited by 114 · see citing works
“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.”
BackgroundMre11 Assembles Linear DNA Fragments into DNA Damage Signaling Complexes
Costanzo, V., Paull, T., Gottesman, M., & Gautier, J. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020110 · Cited by 106 · see citing works
Kerzendorfer, C., & O’Driscoll, M. (2009) · DNA Repair · doi:10.1016/j.dnarep.2009.04.018 · Cited by 97 · see citing works
Cervelli, T., Palacios, J. A., Zentilin, L., Mano, M., Schwartz, R. A., Weitzman, M. D., & Giacca, M. (2008) · Journal of Cell Science · doi:10.1242/jcs.003632 · Cited by 84 · see citing works
A domain of Rad9 specifically required for activation of Chk1 in budding yeast
Blankley, R. T., & Lydall, D. (2004) · Journal of Cell Science · doi:10.1242/jcs.00907 · Cited by 69 · see citing works
NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway
Wilson, K. A., & Stern, D. F. (2008) · Cell Cycle · doi:10.4161/cc.7.22.7102 · Cited by 43 · see citing works
- Authors
- Goldberg, M., Stucki, M., Falck, J., D'Amours, D., Rahman, D., Pappin, D., Bartek, J., & Jackson, S. P.
- Affiliations
- University of Cambridge (GB)
- Danish Cancer Society (DK)
- Imperial College London (GB)
- Corresponding author
- Jackson, Stephen P.
- Venue
- Nature
- Published
- 2003-02
- Volume
- 421
- Issue
- 6926
- Pages
- 952-956
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2077709632
- Cited by
- 506
- References
- 4
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 7 · 2020: 10 · 2019: 11 · 2018: 15 · 2017: 13 · 2016: 13 · 2015: 15 · 2014: 23 · 2013: 20 · 2012: 28
- FWCI
- 16.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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, Mre11 complex, S-phase checkpoint, DNA damage checkpoint, ionizing radiation, ATM phosphorylation, radioresistance (biology), DNA repair, nuclear foci, BRCT domain, FHA domain, 53BP1, H2AX phosphorylation, Chk2, SMC1A, NBS1
- MeSH terms
- MRE11 Homologue Protein, Structural Maintenance of Chromosome Protein 1, Animals, Cell Line, Chromosomal Proteins, Non-Histone, DNA Damage, DNA-Binding Proteins, Humans, Nuclear Proteins, Phosphorylation, Protein Kinases, Radiation, Ionizing, Tumor Cells, Cultured, Trans-Activators, S Phase, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Cell Cycle Proteins, cdc25 Phosphatases, DNA Repair Enzymes, 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
