MDC1
| MDC1 | |||
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Gene ontology | |||
| Molecular function | |||
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| Sources:Amigo / QuickGO | |||
| View/Edit Human | View/Edit Mouse |
Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene[5][6][7] located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).
Function
Role in DNA damage response
The MDC1 gene encodes the MDC1
DNA damage, and signal the repair mechanism as well as activating cell cycle checkpoints.[9] The MDC1s role in DDR is to function both as a mediator/adaptor protein mediating a complex of other DDR proteins at the site of DNA damage[9] and repairing DNA damage through its PST domain.[10]
When a cell is exposed to
DNA damage
.
Role in apoptosis
MDC1 has anti-apoptotic properties by directly inhibiting the
MDM2.[11]
MDC1 can execute its anti-apoptotic activity by inhibiting p53 in two ways. The MDC1 protein can bind to the n-terminus of p53 through its BRC1 domain which blocks p53 transactivation domain. MDC1 can also inactivate p53 by reducing the phosphorylation levels of p53 Ser-15 residues necessary to p53 apoptotic activity.
Studies on lung cancer cell lines (genotoxic agents when MDC1 protein levels were reduced with siRNA.[11]
Role in meiosis
In female mammals, a unique characteristic of
chromosomes.[12]
Loss of MDC1 protein
Inhibition or loss of MDC1 protein through studies with
siRNA on human cells or knockout studies in mice have shown several defects at both the cellular and organismal level. Mice lacking MDC1 are smaller, have infertile males, are radiosensitive, and are more susceptible to tumors. Knock out MDC1 mice cells and silenced human cells were radiosensitive, failed to initiate Intra-S phase and G2/M checkpoints, failed to produce ionizing radiation-induced foci had poor phosphorylation by the DRR kinases (ATM, CHK1, CHK2), defects in homologous recombination. Human cells with silenced MDC1 also displayed random plasmid integration, reduced apoptosis, and slowed mitosis.[9]
Interactions
MDC1 has been shown to
interact
with:
MDC1 also binds to mRNA or polyadenylated RNA in the nucleus.[15]
Protein structure
The MDC1 protein contains the following domains listed in order from N-terminal to C-terminal:
- forkhead-associated domain (FHA), N-terminus domain lies between amino acid residues 54 and 105
- SDT (or SDTD) - This domain is located between amino acids 218 and 460.
- TQXF- This domain is located between amino acids 699 and 768.
- PST- This domain lies between amino acid residues 114 and 1662.
- BRCA 1 C-terminus (BRCT) domain and lies between amino acids 1891 and 2082.
- FHA domain
- Unlike the FHA domains on other DRR factors, the FHA domain on MDC1 is not well-characterized. It has been implicated in DSB repair, Intra-S phase and G2/M checkpoints but the specific mechanism is yet to be determined. The FHA domain does have a few putative MDC1-FHA interacting factors such as
- SDT domain
- When the SDT domain is phosphorylated it can bind the NBS1 of the MRN complex are necessary for the activation of intra-S-phase and the G2/M checkpoints, however their role in the molecular mechanism of checkpoint control has not been resolved.[9]
- TQXF domain
- This domain is characterized by four threonine-glutamine then a phenylalanine at the 3+ position.ATM phosphorylates this domain allowing it to bind RNF8 an E3 ubiquitin ligase. This MDC1/RNF8 coupling then facilitates the recruitment of other DDR factors such as RNF168, 53BP1, and BRCA1.[9] TQXF is important for proper passage through the G2/M checkpoint, however the molecular mechanism through which MDC1 and RNF8 regulate the G2/M checkpoint has not yet been resolved.
- PST domain
- The PST domain is composed of repeats of a proline-serine-threonine motif. This domain plays a role in DNA repair by both homologous recombination and by Non-homologous end joining, however the mechanism through which it facilitates repair of damaged DNA is not yet known.[10]
- BRCT domain
- The BRCT domain on MDC1 directly binds to the γH2AX of damaged chromatin. The BRCT domain creates an α/β fold which extends from the C-terminus of MDC1 through a linker region. It preferentially binds to phosphorylated Ser residues followed by Glu, Tyr, motif on γH2AX.
Regulation
MDC1 is indirectly down regulated by the
mRNA inhibiting translation. Aberrant overexpression of AKT1, which is observed in several cancers including breast, lung and prostate, results in reduced production of MDC1 and subsequently a destabilization of the genome and increased tumorigenicity.[23]
Role in cancer
MDC1 is a putative tumor suppressor. Knockout studies in mice have shown an increase in tumor development when MDC1 is lost. Reduction in MDC1 protein levels has been observed in a large number of breast and lung carcinomas.siRNA. Because of MDC1s involvement in several pathways that are often misappropriated by cancer cells including the cell cycle checkpoints, DDR, and p53 tumor suppression, cancer treatments that target MDC1 have the potential to be potent radiosensitizer and chemosensitizer.
References
- ^ a b c ENSG00000237095, ENSG00000137337, ENSG00000206481, ENSG00000234012, ENSG00000231135, ENSG00000228575, ENSG00000225589 GRCh38: Ensembl release 89: ENSG00000224587, ENSG00000237095, ENSG00000137337, ENSG00000206481, ENSG00000234012, ENSG00000231135, ENSG00000228575, ENSG00000225589 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000061607 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 10975465.
- ^ S2CID 4410773.
- ^ "Entrez Gene: MDC1 mediator of DNA damage checkpoint 1".
- S2CID 4419141.
- ^ S2CID 20619554.
- ^ PMID 15377652.
- ^ PMID 17535811.
- ^ PMID 36999590.
- S2CID 4411622.
- ^ S2CID 24870579.
- PMID 27040163.
- PMID 11741547.
- PMID 16618811.
- S2CID 4301037.
- PMID 15201865.
- PMID 16427009.
- PMID 17827148.
- PMID 19098900.
- PMID 25627978.
- PMID 18504301.
- PMID 17546051.
- S2CID 27389033.
- S2CID 16067442.
Further reading
- Stucki M, Jackson SP (2005). "MDC1/NFBD1: a key regulator of the DNA damage response in higher eukaryotes". DNA Repair (Amst.). 3 (8–9): 953–957. PMID 15279781.
- Nagase T, Seki N, Ishikawa K, Tanaka A, Nomura N (1996). "Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1". DNA Res. 3 (1): 17–24. PMID 8724849.
- Shang YL, Bodero AJ, Chen PL (2003). "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". J. Biol. Chem. 278 (8): 6323–6329. PMID 12475977.
- Xu X, Stern DF (2003). "NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways". J. Biol. Chem. 278 (10): 8795–8803. PMID 12499369.
- Peng A, Chen PL (2003). "NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage". J. Biol. Chem. 278 (11): 8873–8876. PMID 12551934.
- Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP (2003). "MDC1 is required for the intra-S-phase DNA damage checkpoint". Nature. 421 (6926): 952–956. S2CID 4301037.
- Lou Z, Minter-Dykhouse K, Wu X, Chen J (2003). "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways". Nature. 421 (6926): 957–961. S2CID 4411622.
- Lou Z, Chini CC, Minter-Dykhouse K, Chen J (2003). "Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control". J. Biol. Chem. 278 (16): 13599–13602. PMID 12611903.
- Xu X, Stern DF (2003). "NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors". FASEB J. 17 (13): 1842–1848. S2CID 24870579.
- Rodriguez M, Yu X, Chen J, Songyang Z (2004). "Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains". J. Biol. Chem. 278 (52): 52914–52918. PMID 14578343.
- Mochan TA, Venere M, DiTullio RA, Halazonetis TD (2004). "53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage". Cancer Res. 63 (24): 8586–91. PMID 14695167.
- Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson SP, Bartek J, Lukas J (2005). "Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention". EMBO J. 23 (13): 2674–2683. PMID 15201865.
- Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (2004). "Large-scale characterization of HeLa cell nuclear phosphoproteins". Proc. Natl. Acad. Sci. U.S.A. 101 (33): 12130–12135. PMID 15302935.
- Lou Z, Chen BP, Asaithamby A, Minter-Dykhouse K, Chen DJ, Chen J (2004). "MDC1 regulates DNA-PK autophosphorylation in response to DNA damage". J. Biol. Chem. 279 (45): 46359–46362. PMID 15377652.
- Polci R, Peng A, Chen PL, Riley DJ, Chen Y (2005). "NIMA-related protein kinase 1 is involved early in the ionizing radiation-induced DNA damage response". Cancer Res. 64 (24): 8800–8803. PMID 15604234.
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