Affinage

MDC1

Mediator of DNA damage checkpoint protein 1 · UniProt Q14676

Length
2089 aa
Mass
226.7 kDa
Annotated
2026-06-10
100 papers in source corpus 49 papers cited in narrative 49 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MDC1 is a large nuclear scaffold protein that orchestrates the chromatin-based response to DNA double-strand breaks (DSBs) by reading the γH2AX mark and nucleating downstream repair and checkpoint machinery (PMID:16377563, PMID:16049003, PMID:12499369). Its tandem BRCT repeats directly and specifically recognize the phosphorylated C-terminal tail of γH2AX, an interaction structurally dependent on Arg1932/Arg1933 contacting both the phosphate and the free C-terminal carboxylate of the H2AX tail — a stringent specificity that distinguishes MDC1 from BRCA1-type BRCT readers (PMID:16377563, PMID:16049003, PMID:20159462). This recognition, supported by MOF-dependent H4K16 acetylation and the H2AX acidic patch, immobilizes MDC1 on damage-flanking chromatin and converts transient factor recruitment into sustained retention (PMID:15201865, PMID:20837706). Through its FHA domain MDC1 binds and concentrates activated ATM at breaks, driving a positive-feedback loop that amplifies local H2AX phosphorylation and γH2AX spreading (PMID:16427009, PMID:19450528). MDC1 then functions as a recruitment platform: CK2-phosphorylated SDT repeats engage the NBS1 FHA/BRCT domains to retain the MRN complex (PMID:18583988, PMID:18411308, PMID:18411307, PMID:18678890), the same phospho-repeats recruit TOPBP1 and aprataxin (PMID:21482717, PMID:23891287, PMID:20008512), and its BRCT/repeat regions support 53BP1, RNF8, RAP80–BRCA1 and Rad51 accumulation to drive checkpoint activation and homologous recombination (PMID:16009723, PMID:18986980, PMID:16186822, PMID:19797077, PMID:21622030). MDC1 acts genetically upstream of 53BP1 in the ATM cascade and specializes in γH2AX-dependent homologous recombination, with MDC1-null mice phenocopying H2AX loss (PMID:16427009, PMID:18158901, PMID:18504301). MDC1 self-association is regulated by ATM-dependent phosphorylation — pThr4 drives FHA-mediated dimerization and pThr98 promotes oligomerization, both required for efficient focus formation and checkpoint signaling (PMID:22234877, PMID:22234878, PMID:21705321). Abundance and chromatin dwell-time are tuned by a SUMO–ubiquitin axis: DNA-damage-induced SUMOylation at Lys1840 targets MDC1 for RNF4-dependent ubiquitylation and removal, counteracted by the deubiquitylase ataxin-3, while Lys45 methylation/demethylation by EHMT1/2 and JMJD1C governs the MDC1–ATM interaction and the RAP80–BRCA1 branch (PMID:22635276, PMID:28275011, PMID:24240613, PMID:30022091). Beyond canonical DSB signaling, MDC1 contributes to meiotic sex chromosome inactivation, mitotic kinetochore/spindle-checkpoint control and APC/C–Cdc20-regulated metaphase-to-anaphase transition, and acts as an androgen-receptor co-activator (PMID:21536735, PMID:24509855, PMID:17827148, PMID:19826003, PMID:25934801).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 High

    Established MDC1 as a domain-defined DDR mediator: its FHA and BRCT domains link it to activated CHK2 and to the MRN complex, and its loss produces radioresistant DNA synthesis and checkpoint defects, defining MDC1 as a core node of the ATM–CHK2 axis.

    Evidence Co-IP, phosphopeptide binding, siRNA knockdown with mutant rescue, and checkpoint/RDS assays across three concurrent papers

    PMID:12607003 PMID:12607004 PMID:12607005

    Open questions at the time
    • Did not resolve the molecular basis of MDC1 recruitment to chromatin
    • MRN binding mechanism (the SDT/CK2 link) not yet defined
  2. 2004 High

    Defined the physical logic of MDC1 retention: H2AX-dependent immobilization of MDC1 converts transient NBS1 recruitment into sustained chromatin retention, explaining how breaks generate persistent repair foci.

    Evidence FRAP live-cell imaging, chromatin fractionation, and siRNA epistasis

    PMID:15201865

    Open questions at the time
    • The direct MDC1–chromatin contact (γH2AX vs other) not yet structurally defined
    • Did not address how NBS1 binds MDC1 biochemically
  3. 2005 High

    Provided the structural basis of damage recognition: MDC1 tandem BRCT repeats directly read the phosphorylated γH2AX C-terminus via Arg1932/Arg1933 and an absolute requirement for the free C-terminal carboxylate, the founding event that anchors MDC1 at breaks.

    Evidence X-ray crystallography (1.45 Å), phosphopeptide binding assays, mutagenesis, and focus-formation rescue

    PMID:16049003 PMID:16377563

    Open questions at the time
    • Did not show how BRCT-anchored MDC1 propagates the signal to ATM and downstream factors
  4. 2005 High

    Placed MDC1 upstream of 53BP1 and Rad51 in focus assembly, showing MDC1 governs the dynamic retention of these effectors at breaks.

    Evidence Real-time microscopy with FRAP kinetics, Co-IP, and HR repair assays

    PMID:16009723 PMID:16186822

    Open questions at the time
    • Rad51 interaction is Medium-confidence single-lab
    • Mechanism distinguishing direct vs indirect 53BP1 recruitment not resolved
  5. 2006 High

    Demonstrated the ATM amplification loop and organismal relevance: MDC1 bridges γH2AX (BRCT) and ATM (FHA) to concentrate active ATM at breaks, and MDC1-null mice phenocopy H2AX loss.

    Evidence MDC1-/- mouse knockout, domain-binding analysis, ATM Co-IP, and epistasis with H2AX-/- mice

    PMID:16427009

    Open questions at the time
    • Did not define the spatial extent of γH2AX spreading controlled by MDC1
    • Telomeric and meiotic roles not yet examined
  6. 2008 High

    Resolved how MDC1 recruits MRN: CK2 constitutively phosphorylates MDC1 SDT repeats, which directly engage the NBS1 FHA/BRCT module — a phospho-switch necessary for MRN retention at breaks.

    Evidence In vitro CK2 kinase assays, direct phosphopeptide binding, SDT-motif mutagenesis, and focus formation across multiple concurrent papers

    PMID:18411307 PMID:18411308 PMID:18583988 PMID:18678890

    Open questions at the time
    • Did not establish whether the same SDT repeats serve other FHA-domain partners simultaneously
  7. 2007 High

    Separated mediator specialization: MDC1 drives γH2AX-dependent homologous recombination distinct from 53BP1-dependent NHEJ, clarifying the division of labor among DSB mediators.

    Evidence Genetic epistasis with double mutants and HR-vs-NHEJ repair assays

    PMID:18158901

    Open questions at the time
    • Did not reconcile MDC1's HR role with its upstream control of 53BP1 focus formation
  8. 2009 High

    Quantified the γH2AX self-reinforcing mechanism: MDC1 retains active ATM near breaks to sustain high-density local H2AX phosphorylation but is dispensable for distal spreading.

    Evidence MDC1-knockout cells, γH2AX density ChIP mapping, and epistasis with ATM and DNA-PKcs

    PMID:19450528

    Open questions at the time
    • Did not define the boundary elements limiting γH2AX domains
  9. 2011 High

    Defined MDC1 self-association as a regulatory layer: ATM-driven pThr4 FHA dimerization and pThr98 oligomerization are required for efficient focus assembly and checkpoint signaling.

    Evidence Crystallography of the FHA dimer, ATM phospho-site mapping, mutagenesis, and focus/checkpoint assays

    PMID:21705321 PMID:22234877 PMID:22234878

    Open questions at the time
    • The opposing positive/negative effects of dimerization on FHA-mediated partner binding not fully reconciled
  10. 2012 High

    Established SUMO-targeted turnover as the off-switch: DNA-damage SUMOylation of MDC1 at Lys1840 recruits RNF4 to ubiquitylate and remove MDC1, balancing HR-promoting factor accumulation against 53BP1.

    Evidence In vivo SUMOylation assays, K1840R mutagenesis, RNF4 Co-IP, and HR rescue by 53BP1 downregulation

    PMID:22635276

    Open questions at the time
    • Did not identify the deubiquitylase counteracting RNF4 (later shown to be ataxin-3)
  11. 2013 High

    Identified Lys45 methylation dynamics as a tuner of the ATM/BRCA1 branch: JMJD1C demethylates MDC1 at Lys45 to promote RNF8-dependent ubiquitylation and RAP80–BRCA1 recruitment.

    Evidence In vitro demethylation, Co-IP, mass-spec site identification, and branch-specific cellular epistasis

    PMID:24240613

    Open questions at the time
    • The opposing methyltransferase activity at Lys45 not yet identified in this study
  12. 2017 High

    Closed the SUMO–ubiquitin regulatory circuit: ataxin-3 acts as a SUMO-dependent deubiquitylase that counteracts RNF4 to stabilize MDC1 on chromatin, and ASF1a promotes ATM-dependent MDC1 phosphorylation to license RNF8/168-driven repair.

    Evidence FRAP dwell-time, in vitro SUMO binding, double-knockdown epistasis with RNF4, and NHEJ/HR assays

    PMID:28275011 PMID:28943310

    Open questions at the time
    • ASF1a role is Medium-confidence single-lab
    • Interplay between ataxin-3 stabilization and RNF4/JMJD1C turnover not integrated
  13. 2019 High

    Revealed an H2AX-independent chromatin tether: the MDC1 PST-repeat region binds the nucleosome acidic patch, providing a backup recruitment route critical for 53BP1 recruitment and survival when γH2AX signaling is absent.

    Evidence CRISPR-engineered PST-deletion and H2AX-knockout cells, nucleosome pulldowns, and clonogenic survival

    PMID:31729360

    Open questions at the time
    • Relative contribution of acidic-patch binding versus γH2AX reading under normal conditions not quantified
  14. 2019 High

    Extended MDC1–TOPBP1 function into mitosis: a CK2-phosphorylated MDC1 surface recruits TOPBP1 to tether mitotic DSBs via filamentous bridges, deferring repair to G1 and guarding genome stability.

    Evidence CRISPR mutagenesis, Co-IP, super-resolution imaging, and chromosomal instability/clonogenic assays comparing mitosis vs interphase

    PMID:21482717 PMID:23891287 PMID:30898438

    Open questions at the time
    • How the mitotic DSB tether is resolved upon G1 entry not mechanistically defined
  15. 2011 Medium

    Broadened MDC1's roles beyond canonical DSB signaling into meiotic sex chromosome inactivation, mitotic checkpoint/kinetochore control, APC/C-regulated anaphase onset, and nuclear-receptor co-activation.

    Evidence MDC1-knockout mice (MSCI), kinetochore localization and SAC assays, APC/C activity assays, and AR co-activator Co-IP/ChIP across several papers

    PMID:17827148 PMID:19826003 PMID:21536735 PMID:24509855 PMID:25934801

    Open questions at the time
    • Several of these non-canonical roles rest on single-lab Medium-confidence evidence
    • Whether DDR scaffolding and mitotic/transcriptional roles use shared or distinct MDC1 surfaces is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory layers (FHA dimerization, SDT phosphorylation, Lys45 methylation, SUMO/ubiquitin turnover, acidic-patch binding) are integrated in time and space to set the lifetime and effector output of a single MDC1 focus remains unresolved.
  • No unified quantitative model of MDC1 focus dynamics
  • Crosstalk between turnover and methylation regulation not reconstituted
  • Substrate/partner choice among shared phospho-repeats not deconvolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 6 GO:0042393 histone binding 4 GO:0003677 DNA binding 3 GO:0098772 molecular function regulator activity 3 GO:0140110 transcription regulator activity 1
Localization
GO:0000228 nuclear chromosome 4 GO:0005694 chromosome 2 GO:0005634 nucleus 1
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-1640170 Cell Cycle 3 R-HSA-1474165 Reproduction 2 R-HSA-4839726 Chromatin organization 2
Partners
53BP1ATMH2AXNBS1RAD51RAP80RNF8TOPBP1
Complex memberships
APC/CMRN complex (MRE11-RAD50-NBS1) — binding partner platformmitotic checkpoint complex (kinetochore)

Evidence

Reading pass · 49 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 MDC1 BRCT repeat domain directly binds the phosphorylated C-terminal tail of histone H2AX (γH2AX) in a phosphorylation-dependent manner; X-ray crystal structure of the MDC1 BRCT domain in complex with the γH2AX phosphopeptide revealed that Arg1932 and Arg1933 recognize the C-terminal carboxylate and penultimate Glu of H2AX, and this interaction is critically dependent on the free C-terminal carboxylate of Tyr in the γH2AX tail. MDC1-γH2AX complex formation regulates H2AX phosphorylation and is required for normal radioresistance and efficient accumulation of DNA-damage-response proteins on damaged chromatin. X-ray crystallography, biochemical binding assays, cell biology (focus formation, RNAi knockdown), mutagenesis Cell High 16049003 16377563
2005 The tandem BRCT repeats of MDC1 directly bind the phosphorylated γH2AX tail (pSer-Gln-Glu-Tyr-COO−) in a manner critically dependent on the free C-terminal carboxylate of the C-terminal Tyr residue; X-ray crystal structure at 1.45 Å resolution of the MDC1 BRCT repeats was determined, and Arg1932/Arg1933 were identified as key recognition residues for both the phosphate and the C-terminal carboxylate. X-ray crystallography (1.45 Å), in vitro binding assays with phosphopeptides, comparison with BRCA1 BRCT structure The Journal of biological chemistry High 16049003
2003 MDC1 forms complexes with phosphorylated H2AX in a phosphorylation-dependent manner; siRNA depletion of MDC1 impairs formation of 53BP1, BRCA1, and MRN foci, partially by reducing efficient H2AX phosphorylation; MDC1 is required for proper intra-S phase and G2/M checkpoint activation and Chk1 regulation after ionizing radiation. siRNA knockdown, immunofluorescence (focus formation), phosphopeptide binding assay, cell cycle checkpoint assays Nature High 12607005
2003 MDC1 (KIAA0170) contains FHA and BRCT domains; its FHA domain mediates binding to phosphorylated Thr68 of activated CHK2; MDC1 is phosphorylated in an ATM/CHK2-dependent manner after DNA damage; MDC1 suppression causes defective S-phase checkpoint and reduced apoptosis restored only by wild-type MDC1 but not FHA-deleted MDC1; MDC1 is upstream of p53 stabilization in the ATM-CHK2 pathway. Co-immunoprecipitation, phosphopeptide binding, siRNA knockdown, rescue experiments with deletion mutants, cell cycle and apoptosis assays Nature High 12607004
2003 MDC1 (KIAA0170/NFBD1) binds the MRE11 complex (MRE11-RAD50-NBS1) as an interaction partner; MDC1 is hyperphosphorylated in an ATM-dependent manner after ionizing radiation; siRNA depletion of MDC1 causes a radio-resistant DNA synthesis (RDS) phenotype and prevents ionizing radiation-induced MRE11 complex focus formation; overexpression of the MDC1 FHA domain acts dominantly to interfere with MDC1 and MRE11 focus formation and induces RDS; MDC1-mediated MRN focus formation is crucial for efficient intra-S-phase checkpoint activation. Protein interaction (co-immunoprecipitation), siRNA knockdown, dominant-negative overexpression, RDS assay, focus formation assays Nature High 12607003
2006 MDC1 directly mediates the interaction between γH2AX and ATM through its BRCT domain (γH2AX binding) and FHA domain (ATM binding), forming a positive feedback loop in which MDC1 accumulates activated ATM at DSB sites to facilitate further ATM-dependent H2AX phosphorylation and signal amplification. MDC1-knockout mice recapitulate H2AX-/- phenotypes including growth retardation, male infertility, immune defects, chromosome instability, and radiation sensitivity. Gene knockout (MDC1-/- mice), domain-function analysis (BRCT and FHA binding assays), epistasis with H2AX-/- mice, ATM co-immunoprecipitation Molecular cell High 16427009
2004 MDC1 functions as an H2AX-dependent interaction platform enabling a switch from transient, MDC1-independent recruitment of NBS1 to DSBs to sustained, MDC1-dependent retention of NBS1 in DSB-flanking chromatin. MDC1 becomes partially immobilized (chromatin-bound) after DSB generation in an H2AX-dependent manner; depletion of H2AX prevents MDC1 relocalization and uncouples NBS1 from DSB-flanking chromatin. Live-cell imaging (FRAP), siRNA knockdown, chromatin fractionation, focus formation assays The EMBO journal High 15201865
2008 MDC1 is phosphorylated by casein kinase 2 (CK2) on a cluster of conserved repeat motifs (SDT repeats); this CK2-dependent phosphorylation promotes direct, phosphorylation-dependent interaction with the FHA and twin BRCT domains of NBS1; mutation of the CK2-targeted motifs in MDC1 or CK2 depletion disrupts MDC1-NBS1 interaction and abrogates accumulation of the MRN complex at DSB sites in vivo. In vitro kinase assay (CK2 phosphorylation), direct binding assay, siRNA knockdown of CK2, mutagenesis of MDC1 SDT motifs, focus formation assays, Co-IP EMBO reports High 18411307 18411308 18583988
2008 MDC1 contains multiple conserved acidic sequence motifs (SDT repeats) that are constitutively phosphorylated by CK2 in vitro and in vivo; these phosphorylated SDT motifs directly interact with the N-terminal FHA domain of NBS1 in a phosphorylation-dependent manner; mutation of these motifs or CK2 depletion disrupts MDC1-NBS1 interaction and abrogates MRN complex focus formation at DSBs. In vitro kinase assay (CK2), direct binding (GST pulldown with phosphopeptides), siRNA knockdown of CK2, mutagenesis of MDC1 SDT motifs, focus formation assays The Journal of cell biology High 18411308
2008 NBS1 interacts with MDC1 N-terminal SDT repeats constitutively; this interaction is mediated by phosphorylated SDT repeats binding to the NBS1 FHA domain; phosphorylation of SDT repeats by CK2 is sufficient to trigger MDC1-NBS1 interaction in vitro; MDC1 associates with CK2 activity in cells; disruption of the SDT phosphoacceptor sites prevents NBS1 retention at DSBs. In vitro binding assay, in vitro kinase assay, CK2 inhibition, mutagenesis of MDC1 SDT repeats, focus formation, Co-IP The Journal of cell biology High 18411307
2008 MDC1 directly binds to NBS1 through a region (residues 200-420) containing multiple CK2 phosphorylation sites; this interaction requires both the FHA and tandem BRCT domains of NBS1; disruption of the MDC1-NBS1 interaction results in failure of NBS1 accumulation at DSBs and impairment of intra-S checkpoint activation. Direct binding assay, domain mapping (deletion mutants), siRNA, focus formation, S-phase checkpoint assay Proceedings of the National Academy of Sciences of the United States of America High 18678890
2005 MDC1 controls the dynamic assembly and sustained retention of 53BP1 at DSB sites; siRNA depletion of MDC1 drastically impairs 53BP1 redistribution to DSBs and causes premature dissociation of 53BP1. Real-time microscopy showed 53BP1 assembly at DSBs significantly lags behind MDC1, establishing MDC1 as an upstream determinant of 53BP1 interaction with DSBs. Real-time live-cell microscopy, siRNA knockdown, quantitative single-cell imaging, FRAP The Journal of cell biology High 16009723
2008 53BP1 directly interacts with MDC1 through the tandem BRCT domain of MDC1 and residues 1288-1409 of 53BP1; this interaction is reduced following DSB induction (competition with γH2AX for BRCT binding) and is enhanced during mitosis in a phospho-dependent manner; the MDC1-binding region of 53BP1 is required for 53BP1 focus formation at DSB sites. Direct binding assay (in vitro), co-immunoprecipitation, domain mapping with deletion mutants, focus formation assays, cell cycle analysis The Journal of biological chemistry High 18986980
2007 MDC1 functions primarily in homologous recombination/sister chromatid recombination in a manner strictly dependent on its ability to interact with γH2AX; this function does not require 53BP1 or BRCA1 recruitment to γH2AX chromatin. In contrast, 53BP1 functions in XRCC4-dependent NHEJ independently of H2AX, indicating distinct specialization of these two mediators. Genetic epistasis (double mutant analysis), DSB repair assays (HR vs NHEJ), siRNA knockdown, plasmid-based repair assays Molecular cell High 18158901
2004 MDC1 directly interacts with the Ku/DNA-PKcs complex via its repeat region; MDC1 depletion results in defective phospho-DNA-PKcs foci formation and DNA-PKcs autophosphorylation; DNA-PK-dependent DNA damage repair is defective in MDC1-depleted cells, indicating MDC1 regulates DNA-PKcs autophosphorylation following DNA damage. Co-immunoprecipitation, siRNA knockdown, focus formation assay, DNA-PKcs autophosphorylation assay, NHEJ repair assay The Journal of biological chemistry Medium 15377652
2005 MDC1 forms a complex with Rad51 through a direct interaction with the MDC1 FHA domain; MDC1 depletion results in impaired Rad51 IRIF formation, reduced nuclear and chromatin-bound Rad51, increased Rad51 protein degradation, and impaired homology-mediated DSB repair; MDC1 functions in Rad51-mediated homologous recombination by retaining Rad51 in chromatin. Co-immunoprecipitation, siRNA knockdown, direct binding assay, Rad51 focus formation, HR repair assay, chromatin fractionation Nature structural & molecular biology Medium 16186822
2009 MDC1 is required for RNF8 recruitment to sites of UV-induced DNA damage, establishing a novel function for MDC1 as a scaffold for RNF8 in the nucleotide excision repair (NER)-dependent DNA damage response, leading to H2A ubiquitination at UV damage sites, 53BP1 and BRCA1 recruitment. Co-immunoprecipitation (MDC1-RNF8 interaction), siRNA knockdown, immunofluorescence, NER assay, UV sensitivity assay The Journal of cell biology Medium 19797077
2011 MDC1 defines the chromosome-wide domain of γH2AX spreading on sex chromosomes during male meiosis, initiates meiotic sex chromosome inactivation (MSCI), and leads to XY body formation. MDC1-dependent chromosome-wide spreading of DDR factors constitutes a second step after MDC1-independent recognition of the unsynapsed axis by ATR, TOPBP1, and γH2AX. Genetic analysis (MDC1-knockout mice), immunofluorescence, ChIP, epistasis with H2AX and ATR Genes & development High 21536735
2012 MDC1 is sumoylated at Lys1840 following DNA damage; this sumoylation is recognized by the SUMO-targeted E3 ubiquitin ligase RNF4, which ubiquitinates MDC1, promoting its degradation and removal from DSB sites; K1840R mutation impairs CtIP, RPA, and Rad51 accumulation at DSBs and causes HR defect that can be rescued by 53BP1 downregulation. In vivo sumoylation assay, mutagenesis (K1840R), siRNA, immunofluorescence (focus formation), HR assay, Co-IP (RNF4-MDC1 interaction) The EMBO journal High 22635276
2013 JMJD1C demethylase demethylates MDC1 at Lys45, promoting MDC1-RNF8 interaction and RNF8-dependent MDC1 ubiquitylation, which is required for recruitment of the RAP80-BRCA1 complex to DSBs. JMJD1C is stabilized by interaction with RNF8 and is recruited to DSBs, specifically regulating the RAP80-BRCA1 branch (not 53BP1 branch) of the DDR. Co-immunoprecipitation, in vitro demethylation assay, siRNA, immunofluorescence, mass spectrometry identification of methylation site Nature structural & molecular biology High 24240613
2018 EHMT1 and EHMT2 (lysine methyltransferases) methylate MDC1 at Lys45; EHMT1 interacts with MDC1 in a manner facilitated by DNA damage-initiated ATM signaling; EHMT2 dominantly modulates MDC1 Lys45 methylation; this methylation promotes the interaction between MDC1 and ATM, expanding activated ATM on damaged chromatin and at dysfunctional telomeres, and is required for accumulation of 53BP1 and RAP80 at DSBs. Co-immunoprecipitation, in vitro methyltransferase assay, siRNA knockdown, mass spectrometry, immunofluorescence Scientific reports Medium 30022091
2012 The MDC1 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; the FHA domain binds in trans to phospho-Thr4 (pT4) at the N-terminus of MDC1 from the other subunit; T4 is phosphorylated primarily by ATM upon DNA damage; MDC1 mutants with impaired dimerization form fewer foci at DNA-damage sites. X-ray crystallography, in vitro binding assay (pT4 peptide), phospho-site mapping (ATM), mutagenesis, focus formation assays, artificial dimerization rescue Nucleic acids research High 22234877 22234878
2012 The MDC1 FHA domain undergoes ATM-dependent dimerization by binding a phosphorylation site near the N-terminus of MDC1 itself; X-ray structures reveal a 'head-to-tail' dimerization mechanism related to pre-activated Chk2; this dimerization both positively and negatively influences MDC1 FHA domain-mediated interactions in human cells. X-ray crystallography, phosphosite identification, in vitro binding assays, cellular interaction studies Nucleic acids research High 22234878
2009 Aprataxin binds to MDC1/NFBD1 through a phosphorylation-dependent interaction mediated by the aprataxin FHA domain and multiple CK2 di-phosphorylated S-D-T-D motifs in MDC1; X-ray structural and mutagenic analysis of the aprataxin FHA domain revealed an unusual FHA binding mechanism mediated by a cluster of basic residues; mutation of aprataxin FHA Arg29 prevented its interaction with MDC1 and recruitment to sites of DNA damage. Co-immunoprecipitation, X-ray crystallography (FHA-pSDpTD peptide complex), mutagenesis (Arg29 mutation), focus formation assay Nucleic acids research High 20008512
2011 MDC1 interacts with TOPBP1 via the 5th BRCT domain (BRCT5) of TopBP1 and the SDT repeats of MDC1; TopBP1 accumulation at stalled replication forks is promoted by the H2AX/MDC1 signaling cascade; MDC1 is important for ATR-dependent Chk1 activation in response to replication stress. Co-immunoprecipitation, domain mapping (deletion mutants), siRNA, focus formation at stalled forks, Chk1 phosphorylation assay The Journal of cell biology Medium 21482717
2013 X-ray crystal structures of TopBP1 tandem BRCT4/5 domains free and in complex with a MDC1 consensus pSDpT phosphopeptide revealed that TopBP1 BRCT4/5 adopts a variant BRCT-BRCT packing interface and recognizes the MDC1 phosphopeptide in a manner distinct from other tandem BRCT-peptide structures; mutations in the phosphate-binding pocket of BRCT5 reduced binding affinity and impaired TopBP1 recruitment to γH2AX foci in cells. X-ray crystallography (TopBP1 BRCT4/5 free and bound to MDC1 pSDpT peptide), fluorescence polarization binding assay, mutagenesis, focus formation assay Structure High 23891287
2019 MDC1 interacts with TOPBP1 via a conserved CK2-phosphorylated protein-interaction surface; disruption of MDC1-TOPBP1 binding causes specific loss of TOPBP1 recruitment to DSBs in mitotic (not interphase) cells, increased micronuclei, chromosomal instability, and mitotic radiosensitivity; TOPBP1 forms filamentous structures that bridge MDC1 foci in mitosis, tethering DSBs until repair is reactivated in G1. CRISPR-Cas9 mutagenesis, Co-immunoprecipitation, super-resolution microscopy, immunofluorescence, chromosomal instability assay, clonogenic survival assay Molecular cell High 30898438
2010 MDC1 directly binds the APC/C (anaphase-promoting complex/cyclosome) E3 ubiquitin ligase through its tandem BRCT domain and the phosphorylated C-terminus of the Cdc27 (APC3) subunit; this interaction is enhanced after DNA damage; phosphopeptides corresponding to γH2AX and Cdc27 C-termini compete for binding to MDC1; MDC1 depletion by siRNA causes metaphase arrest, reduced APC/C activity, and failure of Cdc20 to bind APC/C, establishing MDC1 as a regulator of metaphase-to-anaphase transition. Co-immunoprecipitation, direct binding assay, phosphopeptide competition, siRNA knockdown, APC/C ubiquitin ligase activity assay, cell cycle analysis The Journal of biological chemistry Medium 17827148 19826003
2014 MDC1 localizes to mitotic kinetochores following spindle assembly checkpoint (SAC) activation in an ATM-dependent manner; ATM phosphorylates H2AX at mitotic kinetochores, and this phosphorylation is required for MDC1 kinetochore localization; ATM and MDC1 are needed for kinetochore localization of mitotic checkpoint complex components Mad2 and Cdc20, and for maintenance of MCC integrity. Immunofluorescence (MDC1/Mad2/Cdc20 at kinetochores), siRNA knockdown of ATM and MDC1, H2AX phosphorylation analysis, SAC activation assay, Co-IP (MDC1-MCC interaction) The Journal of biological chemistry Medium 24509855
2010 MDC1 is cleaved by caspase-3 during apoptosis, separating its BRCT and FHA domains; this cleavage constitutes a mechanism for inactivating DNA repair by preventing MDC1 from binding γH2AX and amplifying the DDR in apoptotic cells; MDC1 downregulation increases the apoptotic response to TRAIL. In vitro caspase-3 cleavage assay, immunoblotting, siRNA knockdown, TRAIL-induced apoptosis assay, γH2AX focus formation Cancer research Medium 21148072
2006 MDC1 knockdown reduces accumulation of phosphorylated ATM, 53BP1, and Nbs1 at dysfunctional telomere foci (TIFs); the rate of NHEJ of dysfunctional telomeres is significantly decreased when MDC1 or its chromatin recruitment is inhibited; MDC1 promotes a step in NHEJ after 3' telomeric overhang removal, independently of ATM-dependent cell cycle arrest. siRNA knockdown, immunofluorescence (TIF assay), telomere fusion assay (NHEJ quantification), epistasis with Nbs1/53BP1 knockdowns Genes & development Medium 17158742
2008 MDC1 is ubiquitylated and directed for proteasome-dependent degradation, which drives disassembly of MDC1 foci; ubiquitylated MDC1 associates with chromatin before and after IR; blocking proteasome activity causes persistent MDC1 foci and is associated with abrogated BRCA1 focus recruitment in an RNF8-independent manner. Ubiquitylation assay, proteasome inhibition, chromatin immunoprecipitation, immunofluorescence, immunoblotting The Journal of biological chemistry Medium 18757370
2011 MDC1 is ubiquitylated on K1977 of its tandem BRCT domain in a UBC13-dependent manner; MDC1 directly binds RAP80 through the MDC1 tandem BRCT domain and the ubiquitin-interacting motifs of RAP80; this interaction depends on K63-linked poly-ubiquitin chain formation by UBC13. Co-immunoprecipitation, direct binding assay, ubiquitylation site mapping (K1977), UBC13 inhibition/depletion, domain mapping DNA repair Medium 21622030
2011 ATM phosphorylates MDC1 at Thr98 following DNA damage, which promotes MDC1 oligomerization; oligomerization is important for accumulation of MDC1 complex at DSB sites; T98A mutation abolishes oligomerization and results in defective DNA damage checkpoint activation and increased IR sensitivity. In vitro kinase assay (ATM phosphorylation of T98), mutagenesis (T98A), Co-immunoprecipitation (oligomerization), focus formation assay, checkpoint activation assay, clonogenic survival The Journal of biological chemistry Medium 21705321
2012 MDC1 directly interacts with RAG1 via two binding interfaces: (1) the MDC1 tandem BRCT domain binds the RAG1 C-terminal H2AX-like motif (R1Ct), likely requiring phosphorylation of R1Ct; (2) the MDC1 PST repeats bind the N-terminal non-core region of RAG1 (R1Nt) constitutively. Co-immunoprecipitation, direct binding assay (GST pulldown), domain mapping with deletion mutants The Journal of biological chemistry Medium 22942284
2019 The MDC1 PST-repeat region directly interacts with chromatin via the nucleosome acidic patch, mediating H2AX-independent association of MDC1 with chromatin; this region is dispensable when the canonical γH2AX-MDC1 pathway is operative but becomes critical for 53BP1 recruitment and cell survival following DSB induction when H2AX is absent. CRISPR-Cas9 engineered cell lines (PST deletion, H2AX knockout), chromatin binding assay, nucleosome pulldown, focus formation assay, clonogenic survival Nature communications High 31729360
2010 MOF-mediated acetylation of histone H4 Lys16 and an intact H2A.X acidic pocket are essential for recruitment of MDC1 to DNA damage foci; loss of MOF in conditional knockout cells abolished MDC1 recruitment (and downstream 53BP1, BRCA1 recruitment) despite normal early ATM signaling. Conditional knockout mouse model, derived MEFs, immunofluorescence (focus formation), charge-neutralizing H2AX mutant, epistasis analysis Molecular and cellular biology Medium 20837706
2017 Ataxin-3 (a deubiquitylase) counteracts RNF4-mediated ubiquitylation of MDC1, stabilizing MDC1 at DSBs; loss of ataxin-3 decreases MDC1 chromatin dwell time (reversed by co-depletion of RNF4); ataxin-3 is recruited to DSBs in a SUMOylation-dependent fashion and directly interacts with SUMO in vitro, defining a SUMO-dependent DUB mechanism toward MDC1; ataxin-3 loss reduces RNF8 and RNF168 recruitment and downstream 53BP1/BRCA1 focus formation. siRNA knockdown, Co-IP, in vitro SUMO binding assay, FRAP (chromatin dwell time), double knockdown epistasis, NHEJ/HR repair assays The EMBO journal High 28275011
2017 ASF1a (histone chaperone) interacts with MDC1 and is recruited to DSBs; ASF1a facilitates the interaction of phospho-ATM with MDC1 and the ATM-dependent phosphorylation of MDC1, which is required for RNF8/RNF168 recruitment, histone ubiquitination, 53BP1 recruitment, and NHEJ; this role is specific to ASF1a (not ASF1b) and does not require its histone chaperone activity. Co-immunoprecipitation, siRNA knockdown, phosphorylation assay, ubiquitination assay, NHEJ repair assay, focus formation assay, clonogenic survival Molecular cell Medium 28943310
2007 MDC1 functions upstream of 53BP1 in the DDR pathway; MDC1 regulates 53BP1 focus formation and phosphorylation in response to DNA damage; loss of both MDC1 and 53BP1 does not significantly increase defects in DDR or tumor incidence compared with MDC1 loss alone, placing MDC1 upstream of 53BP1 in the ATM cascade. Double-knockout mouse model (MDC1-/-/53BP1-/-), siRNA, focus formation assay, tumor incidence analysis, DDR signaling assays The Journal of cell biology High 18504301
2010 MDC1 is required for BRCT domain interaction with the APC/C Cdc27 subunit, regulating metaphase-to-anaphase transition; MDC1 depletion causes metaphase arrest independent of BubR1-dependent signaling and ATM/ATR activation, characterized by reduced Cdc20 levels and failure of Cdc20 to bind APC/C. siRNA knockdown, Co-IP (MDC1-APC/C), APC/C ubiquitin ligase activity assay, cell cycle analysis (FACS), immunofluorescence The Journal of biological chemistry Medium 19826003
2015 MDC1 functions as a co-activator of androgen receptor (AR): MDC1 facilitates the association between AR and histone acetyltransferase GCN5, increasing histone H3 acetylation on cis-regulatory elements of AR target genes including p21 and Vinculin; MDC1 knockdown promotes PCa cell growth and migration and decreases expression of a subset of AR-induced target genes. Co-immunoprecipitation (MDC1-AR-GCN5 complex), ChIP (H3 acetylation at AR target gene promoters), siRNA knockdown, gene expression analysis Nucleic acids research Medium 25934801
2007 NFBD1/MDC1 associates with p53 directly; MDC1 BRCT domain binds the N-terminal region of p53 and inhibits p53 Ser15 phosphorylation and p53 transcriptional activity; MDC1 knockdown increases adriamycin sensitivity in p53 wild-type but not p53-deficient cells. Co-immunoprecipitation, luciferase reporter assay (p53 transcription), siRNA knockdown, p53 phosphorylation assay, apoptosis assay The Journal of biological chemistry Medium 17535811
2013 p53 and MDC1 directly interact in vitro; the interaction is mediated by the MDC1 tandem BRCT domain and the C-terminal domain of p53; acetylation of p53 Lys382 and phosphorylation of p53 Ser392 enhance the p53-MDC1 interaction; the p53-MDC1 interaction is augmented upon DNA damage induction in human cells. In vitro direct binding assay (recombinant proteins), co-immunoprecipitation (from cells), modified peptide binding assays PloS one Medium 24194938
2002 NFBD1 (MDC1) is a chromatin-associated protein whose phosphorylation in response to ionizing radiation is ATM-dependent; it forms nuclear foci within 1 minute after IR that colocalize with γH2AX, 53BP1, and MRE11/RAD50 foci; it is modified in G2/M phase or after DNA damage. Immunofluorescence, chromatin fractionation, ATM-dependent phosphorylation assay (with ATM inhibitor/ATM-deficient cells), immunoblotting The Journal of biological chemistry Medium 12499369
2009 MDC1 is essential for γH2AX formation at high densities near DSBs; MDC1 retains activated ATM in chromatin near DSBs to promote continued local phosphorylation of H2AX, fueling a γH2AX self-reinforcing mechanism; MDC1 is not required for γH2AX formation over distal sequences (which requires ATM but not MDC1). Genetic analysis (MDC1-knockout cells), ChIP (γH2AX density mapping), quantitative immunofluorescence, epistasis with ATM and DNA-PKcs Molecular cell High 19450528
2012 The HTLV-1 viral oncoprotein Tax sequesters MDC1 to chromatin sites distinct from normal IRIF through the C-terminal half of Tax, which is critical for MDC1 binding; Tax expression induces H2AX phosphorylation and monoubiquitylation in an MDC1-dependent manner (ablated by siRNA suppression of MDC1); Tax-induced pseudo-DDR competes with normal cellular DDR, repressing Nbs1 IRIF formation. Co-immunoprecipitation, confocal microscopy, siRNA (MDC1), domain mapping (Tax N- and C-terminal mutants), H2AX ubiquitylation assay The Journal of biological chemistry Medium 20729195
2023 In oocyte meiosis I, DSB-induced p-MDC1 and p-TOPBP1 are recruited from spindle poles to chromosomes in a CIP2A-dependent manner; this pole-to-chromosome relocation of the CIP2A-MDC1-TOPBP1 complex requires intact microtubules, kinetochore/centromere components (CENP-A, HEC1), and is regulated by PLK1 (not ATM); disruption of microtubules or CIP2A depletion impairs DSB repair during meiosis I. Immunofluorescence (live oocyte imaging), microtubule depolymerization, siRNA (CIP2A, CENP-A, HEC1), Co-immunoprecipitation (CIP2A-MDC1-TOPBP1), inhibitors (PLK1, ATM), DSB repair assay Nucleic acids research Medium 36999590
2010 Comparison of crystal structures of BRCA1 and MDC1 BRCT domains bound to tetrapeptide substrates revealed that MDC1 has a much stronger preference for a free C-terminal carboxylate at the +3 position compared to BRCA1; a mutation in MDC1 inducing a more BRCA1-like conformation relaxes binding specificity to allow binding of phosphopeptides lacking a free C-terminus. X-ray crystallography (BRCA1 and MDC1 BRCT-peptide complexes), fluorescence polarization binding assay, mutagenesis Structure High 20159462

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 882 16377563
2003 MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 709 12607005
2006 MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Molecular cell 509 16427009
2003 MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 417 12607003
2006 gammaH2AX and MDC1: anchoring the DNA-damage-response machinery to broken chromosomes. DNA repair 339 16531125
2004 Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. The EMBO journal 319 15201865
2003 MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature 286 12607004
2005 Dynamic assembly and sustained retention of 53BP1 at the sites of DNA damage are controlled by Mdc1/NFBD1. The Journal of cell biology 235 16009723
2008 Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. EMBO reports 233 18583988
2008 Constitutive phosphorylation of MDC1 physically links the MRE11-RAD50-NBS1 complex to damaged chromatin. The Journal of cell biology 188 18411308
2007 Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. Molecular cell 186 18158901
2008 Phosphorylation of SDT repeats in the MDC1 N terminus triggers retention of NBS1 at the DNA damage-modified chromatin. The Journal of cell biology 182 18411307
2010 MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Molecular and cellular biology 169 20837706
2009 Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin. Molecular cell 168 19450528
2003 53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Cancer research 168 14695167
2009 Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response. The Journal of cell biology 156 19797077
2011 MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes & development 154 21536735
2012 Sumoylation of MDC1 is important for proper DNA damage response. The EMBO journal 143 22635276
2008 MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks. Proceedings of the National Academy of Sciences of the United States of America 137 18678890
2005 Structure of the BRCT repeat domain of MDC1 and its specificity for the free COOH-terminal end of the gamma-H2AX histone tail. The Journal of biological chemistry 109 16049003
2002 NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. The Journal of biological chemistry 106 12499369
2019 MDC1 Interacts with TOPBP1 to Maintain Chromosomal Stability during Mitosis. Molecular cell 103 30898438
2005 MDC1 interacts with Rad51 and facilitates homologous recombination. Nature structural & molecular biology 101 16186822
2012 BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Molecular and cellular biology 99 23230272
2003 NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 98 14519663
2010 Role of ATM and the damage response mediator proteins 53BP1 and MDC1 in the maintenance of G(2)/M checkpoint arrest. Molecular and cellular biology 96 20421415
2007 DNA damage response mediators MDC1 and 53BP1: constitutive activation and aberrant loss in breast and lung cancer, but not in testicular germ cell tumours. Oncogene 95 17546051
2009 The cellular response to DNA damage: a focus on MDC1 and its interacting proteins. Nucleus (Austin, Tex.) 89 21326949
2007 MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. The Journal of biological chemistry 89 17925396
2004 MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes. DNA repair 89 15279781
2003 NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. The Journal of biological chemistry 89 12551934
2013 JMJD1C demethylates MDC1 to regulate the RNF8 and BRCA1-mediated chromatin response to DNA breaks. Nature structural & molecular biology 86 24240613
2011 MDC1 collaborates with TopBP1 in DNA replication checkpoint control. The Journal of cell biology 85 21482717
2010 MDC1: The art of keeping things in focus. Chromosoma 79 20224865
2008 Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1. Genes & development 79 18283122
2006 MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes & development 76 17158742
2007 Differences in DNA double strand breaks repair in male germ cell types: lessons learned from a differential expression of Mdc1 and 53BP1. DNA repair 75 17376750
2017 Ataxin-3 consolidates the MDC1-dependent DNA double-strand break response by counteracting the SUMO-targeted ubiquitin ligase RNF4. The EMBO journal 72 28275011
2004 MDC1 regulates DNA-PK autophosphorylation in response to DNA damage. The Journal of biological chemistry 69 15377652
2008 Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis. The Journal of cell biology 68 18504301
2002 NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response. The Journal of biological chemistry 68 12475977
2012 Nucleolin participates in DNA double-strand break-induced damage response through MDC1-dependent pathway. PloS one 66 23145133
2011 Primary human mDC1, mDC2, and pDC dendritic cells are differentially infected and activated by respiratory syncytial virus. PloS one 61 21297989
2015 A novel antisense long noncoding RNA regulates the expression of MDC1 in bladder cancer. Oncotarget 57 25514464
2008 Disassembly of MDC1 foci is controlled by ubiquitin-proteasome-dependent degradation. The Journal of biological chemistry 57 18757370
2014 Interplay between the DNA damage proteins MDC1 and ATM in the regulation of the spindle assembly checkpoint. The Journal of biological chemistry 52 24509855
2008 The direct interaction between 53BP1 and MDC1 is required for the recruitment of 53BP1 to sites of damage. The Journal of biological chemistry 51 18986980
2018 LRH1 enhances cell resistance to chemotherapy by transcriptionally activating MDC1 expression and attenuating DNA damage in human breast cancer. Oncogene 49 29545602
2009 CK2 phosphorylation-dependent interaction between aprataxin and MDC1 in the DNA damage response. Nucleic acids research 49 20008512
2010 Comparison of the structures and peptide binding specificities of the BRCT domains of MDC1 and BRCA1. Structure (London, England : 1993) 48 20159462
2015 MDC1 functionally identified as an androgen receptor co-activator participates in suppression of prostate cancer. Nucleic acids research 46 25934801
2019 MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance. Nature communications 45 31729360
2007 NFBD1/MDC1 associates with p53 and regulates its function at the crossroad between cell survival and death in response to DNA damage. The Journal of biological chemistry 45 17535811
2017 SOX9 activity is induced by oncogenic Kras to affect MDC1 and MCMs expression in pancreatic cancer. Oncogene 44 29059173
2007 Genistein-induced neuronal apoptosis and G2/M cell cycle arrest is associated with MDC1 up-regulation and PLK1 down-regulation. European journal of pharmacology 44 17706963
2007 The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome. The Journal of biological chemistry 44 17827148
2022 AP4 suppresses DNA damage, chromosomal instability and senescence via inducing MDC1/Mediator of DNA damage Checkpoint 1 and repressing MIR22HG/miR-22-3p. Molecular cancer 41 35624466
2015 MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1. Cancer research 41 25627978
2012 Structural mechanism of the phosphorylation-dependent dimerization of the MDC1 forkhead-associated domain. Nucleic acids research 41 22234877
2012 Recruitment kinetics of DNA repair proteins Mdc1 and Rad52 but not 53BP1 depend on damage complexity. PloS one 41 22860035
2012 The molecular basis of ATM-dependent dimerization of the Mdc1 DNA damage checkpoint mediator. Nucleic acids research 40 22234878
2009 Mediator of DNA damage checkpoint 1 (MDC1) regulates mitotic progression. The Journal of biological chemistry 40 19826003
2000 NFBD1/KIAA0170 is a novel nuclear transcriptional transactivator with BRCT domain. DNA and cell biology 39 10975465
2011 Recruitment of the cohesin loading factor NIPBL to DNA double-strand breaks depends on MDC1, RNF168 and HP1γ in human cells. Biochemical and biophysical research communications 37 21784059
2021 A Novel Targeted Therapy System for Cervical Cancer:  Co-Delivery System  of  Antisense LncRNA of MDC1 and Oxaliplatin Magnetic Thermosensitive Cationic Liposome Drug Carrier. International journal of nanomedicine 36 33603368
2008 NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway. Cell cycle (Georgetown, Tex.) 36 19001859
2020 Roles for MDC1 in cancer development and treatment. DNA repair 35 32866776
2017 ASF1a Promotes Non-homologous End Joining Repair by Facilitating Phosphorylation of MDC1 by ATM at Double-Strand Breaks. Molecular cell 35 28943310
2012 MDC1 and RNF8 function in a pathway that directs BRCA1-dependent localization of PALB2 required for homologous recombination. Journal of cell science 32 23038782
2008 Replication independent ATR signalling leads to G2/M arrest requiring Nbs1, 53BP1 and MDC1. Human molecular genetics 32 18664457
2015 MDC1 Enhances Estrogen Receptor-mediated Transactivation and Contributes to Breast Cancer Suppression. International journal of biological sciences 31 26221067
2010 The viral oncoprotein tax sequesters DNA damage response factors by tethering MDC1 to chromatin. The Journal of biological chemistry 31 20729195
2010 MDC1 cleavage by caspase-3: a novel mechanism for inactivating the DNA damage response during apoptosis. Cancer research 30 21148072
2011 NFBD1/MDC1 is a protein of oncogenic potential in human cervical cancer. Molecular and cellular biochemistry 28 21853275
2006 Signaling networks controlled by the MRN complex and MDC1 during early DNA damage responses. Molecular carcinogenesis 27 16691596
2005 Specific association of mouse MDC1/NFBD1 with NBS1 at sites of DNA-damage. Cell cycle (Georgetown, Tex.) 26 15611643
2017 ID3 regulates the MDC1-mediated DNA damage response in order to maintain genome stability. Nature communications 25 29026069
2013 Structural insights into recognition of MDC1 by TopBP1 in DNA replication checkpoint control. Structure (London, England : 1993) 24 23891287
2012 A dual interaction between the DNA damage response protein MDC1 and the RAG1 subunit of the V(D)J recombinase. The Journal of biological chemistry 22 22942284
2008 Structure of a second BRCT domain identified in the nijmegen breakage syndrome protein Nbs1 and its function in an MDC1-dependent localization of Nbs1 to DNA damage sites. Journal of molecular biology 22 18582474
2018 H2AFX and MDC1 promote maintenance of genomic integrity in male germ cells. Journal of cell science 21 29437857
2016 MDC1-AS, an antisense long noncoding RNA, regulates cell proliferation of glioma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 27261595
2014 Mdb1, a fission yeast homolog of human MDC1, modulates DNA damage response and mitotic spindle function. PloS one 20 24806815
2011 Oligomerization of MDC1 protein is important for proper DNA damage response. The Journal of biological chemistry 20 21705321
2023 Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes. Nucleic acids research 19 36999590
2022 Oxidant stress-sensitive circRNA Mdc1 controls cardiomyocyte chromosome stability and cell cycle re-entry during heart regeneration. Pharmacological research 19 36058431
2005 NFBD1/Mdc1 mediates ATR-dependent DNA damage response. Cancer research 18 15734998
2022 Wee1 promotes cell proliferation and imatinib resistance in chronic myeloid leukemia via regulating DNA damage repair dependent on ATM-γH2AX-MDC1. Cell communication and signaling : CCS 17 36575478
2015 Silencing NFBD1/MDC1 enhances the radiosensitivity of human nasopharyngeal cancer CNE1 cells and results in tumor growth inhibition. Cell death & disease 17 26247734
2011 53BP1 and MDC1 foci formation in HT-1080 cells for low- and high-LET microbeam irradiations. Radiation and environmental biophysics 17 21559952
2021 Mediator of DNA Damage Checkpoint 1 (MDC1) Is a Novel Estrogen Receptor Coregulator in Invasive Lobular Carcinoma of the Breast. Molecular cancer research : MCR 16 33947745
2018 MDC1 methylation mediated by lysine methyltransferases EHMT1 and EHMT2 regulates active ATM accumulation flanking DNA damage sites. Scientific reports 16 30022091
2008 Sp1-mediated transcriptional regulation of NFBD1/MDC1 plays a critical role in DNA damage response pathway. Genes to cells : devoted to molecular & cellular mechanisms 16 18173747
2017 Mutations in the TP53 gene affected recruitment of 53BP1 protein to DNA lesions, but level of 53BP1 was stable after γ-irradiation that depleted MDC1 protein in specific TP53 mutants. Histochemistry and cell biology 15 28397142
2013 Acetylation of lysine 382 and phosphorylation of serine 392 in p53 modulate the interaction between p53 and MDC1 in vitro. PloS one 15 24194938
2013 A mediator methylation mystery: JMJD1C demethylates MDC1 to regulate DNA repair. Nature structural & molecular biology 15 24304913
2011 MDC1 is ubiquitylated on its tandem BRCT domain and directly binds RAP80 in a UBC13-dependent manner. DNA repair 15 21622030
2019 Loss of NFBD1/MDC1 disrupts homologous recombination repair and sensitizes nasopharyngeal carcinoma cells to PARP inhibitors. Journal of biomedical science 14 30717758
2017 Long non-coding RNA MDC1-AS inhibits human gastric cancer cell proliferation and metastasis through an MDC1-dependent mechanism. Experimental and therapeutic medicine 14 29375682
2016 Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells. Molecular and cellular biochemistry 14 27334757

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