ArticleNucleic acids research2012
Structural mechanism of the phosphorylation-dependent dimerization of the MDC1 forkhead-associated domain.
Article in Nucleic acids research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 49 citations in OpenAlex.
- Article
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- The Autonomous Parvovirus Minute Virus of Mice Localizes to Cellular Sites of DNA Damage Using ATR Signaling.Viruses · 2023Article
- Molecular convergence by differential domain acquisition is a hallmark of chromosomal passenger complex evolution.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Immediate-Early, Early, and Late Responses to DNA Double Stranded Breaks.Frontiers in genetics · 2022Review
- Dynamic recruitment of UFM1-specific peptidase 2 to the DNA double-strand breaks regulated by WIP1.Genome instability & disease · 2022Article
- Article
- Lysine Methyltransferase Inhibitors Impair H4K20me2 and 53BP1 Foci in Response to DNA Damage in Sarcomas, a Synthetic Lethality Strategy.Frontiers in cell and developmental biology · 2021Article
- Ubiquitin and ubiquitin-like molecules in DNA double strand break repair.Cell & bioscience · 2020Review
- MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance.Nature communications · 2019Article
- PTEN Methylation by NSD2 Controls Cellular Sensitivity to DNA Damage.Cancer discovery · 2019Article
- UFL1 promotes histone H4 ufmylation and ATM activation.Nature communications · 2019Article
- RNF126 Quenches RNF168 Function in the DNA Damage Response.Genomics, proteomics & bioinformatics · 2018Article
- Article
- L3MBTL2 orchestrates ubiquitin signalling by dictating the sequential recruitment of RNF8 and RNF168 after DNA damage.Nature cell biology · 2018Article
- Aurora kinase B dependent phosphorylation of 53BP1 is required for resolving merotelic kinetochore-microtubule attachment errors during mitosis.Oncotarget · 2017Article
- DNA Damage Response-Independent Role for MDC1 in Maintaining Genomic Stability.Molecular and cellular biology · 2017Article
- INT6/EIF3E Controls the RNF8-Dependent Ubiquitylation Pathway and Facilitates DNA Double-Strand Break Repair in Human Cells.Cancer research · 2016Article
- Dimerization Mediated by a Divergent Forkhead-associated Domain Is Essential for the DNA Damage and Spindle Functions of Fission Yeast Mdb1.The Journal of biological chemistry · 2015Article
- BCL10 regulates RNF8/RNF168-mediated ubiquitination in the DNA damage response.Cell cycle (Georgetown, Tex.) · 2014Article
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
MDC1 is a key mediator of the DNA-damage response in mammals with several phosphorylation-dependent protein interaction domains. The function of its N-terminal forkhead-associated (FHA) domain remains elusive. Here, we show with structural, biochemical and cellular data that the FHA domain mediates phosphorylation-dependent dimerization of MDC1 in response to DNA damage. Crystal structures of the FHA domain reveal a face-to-face dimer with pseudo-dyad symmetry. We found that the FHA domain recognizes phosphothreonine 4 (pT4) at the N-terminus of MDC1 and determined its crystal structure in complex with a pT4 peptide. Biochemical analysis further revealed that in the dimer, the FHA domain binds in trans to pT4 from the other subunit, which greatly stabilizes the otherwise unstable dimer. We show that T4 is phosphorylated primarily by ATM upon DNA damage. MDC1 mutants with the FHA domain deleted or impaired in its ability to dimerize formed fewer foci at DNA-damage sites, but the localization defect was largely rescued by an artificial dimerization module, suggesting that dimerization is the primary function of the MDC1 FHA domain. Our results suggest a novel mechanism for the regulation of MDC1 function through T4 phosphorylation and FHA-mediated dimerization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.