Human Gene MDC1 (ENST00000376406.8) from GENCODE V44
Description: Homo sapiens mediator of DNA damage checkpoint 1 (MDC1), mRNA. (from RefSeq NM_014641) RefSeq Summary (NM_014641): The protein encoded by this gene contains an N-terminal forkhead domain, two BRCA1 C-terminal (BRCT) motifs and a central domain with 13 repetitions of an approximately 41-amino acid sequence. The encoded protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage. This nuclear protein interacts with phosphorylated histone H2AX near sites of DNA double-strand breaks through its BRCT motifs, and facilitates recruitment of the ATM kinase and meiotic recombination 11 protein complex to DNA damage foci. [provided by RefSeq, Jul 2008]. Gencode Transcript: ENST00000376406.8 Gencode Gene: ENSG00000137337.16 Transcript (Including UTRs) Position: hg38 chr6:30,699,807-30,717,281 Size: 17,475 Total Exon Count: 15 Strand: - Coding Region Position: hg38 chr6:30,700,465-30,715,175 Size: 14,711 Coding Exon Count: 14
ID:MDC1_HUMAN DESCRIPTION: RecName: Full=Mediator of DNA damage checkpoint protein 1; AltName: Full=Nuclear factor with BRCT domains 1; FUNCTION: Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AFX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1. SUBUNIT: Homodimer. Interacts with several proteins involved in the DNA damage response, although not all these interactions may be direct. Interacts with H2AFX, which requires phosphorylation of H2AFX on 'Ser-139'. Interacts with the MRN complex, composed of MRE11A/MRE11, RAD50, and NBN. Interacts with CHEK2, which requires ATM-mediated phosphorylation of 'Thr-68' within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164. When phosphorylated, interacts with APTX (via FHA-like domain). INTERACTION: Q13315:ATM; NbExp=2; IntAct=EBI-495644, EBI-495465; P16104:H2AFX; NbExp=6; IntAct=EBI-495644, EBI-494830; O60934:NBN; NbExp=8; IntAct=EBI-495644, EBI-494844; O43070:nbs1 (xeno); NbExp=2; IntAct=EBI-495644, EBI-2125045; O76064:RNF8; NbExp=11; IntAct=EBI-495644, EBI-373337; SUBCELLULAR LOCATION: Nucleus. Note=Associated with chromatin. Relocalizes to discrete nuclear foci following DNA damage, this requires 'Ser-139' phosphorylation of H2AFX. Colocalizes with APTX at sites of DNA double-strand breaks. TISSUE SPECIFICITY: Highly expressed in testis. DOMAIN: Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by 'Ser-139' phosphorylation of H2AFX. PTM: Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain. PTM: Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation. PTM: Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination. SIMILARITY: Contains 2 BRCT domains. SIMILARITY: Contains 1 FHA domain. SEQUENCE CAUTION: Sequence=BAA11487.2; Type=Erroneous initiation; Sequence=CAH18685.1; Type=Erroneous termination; Positions=1804; Note=Translated as Gln;
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q14676
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0006281 DNA repair GO:0006303 double-strand break repair via nonhomologous end joining GO:0006974 cellular response to DNA damage stimulus GO:0007049 cell cycle GO:0031573 intra-S DNA damage checkpoint
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