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MDC1

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 H2AX.

Function

Histone reader protein 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 (PubMed:12475977, PubMed:12499369, PubMed:12551934, PubMed:12607003, PubMed:12607004, PubMed:12607005, PubMed:12611903, PubMed:14695167, PubMed:15201865, PubMed:15377652, PubMed:16049003, PubMed:16377563, PubMed:30898438). Specifically recognizes and binds histone H2AX phosphorylated at 'Ser-139', a marker of DNA damage, serving as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage sites (PubMed:12607005, PubMed:15201865, PubMed:16049003, PubMed:16377563, PubMed:30898438). Also required for downstream events subsequent to the recruitment of these proteins (PubMed:12607005, PubMed:15201865, PubMed:16049003, PubMed:16377563, PubMed:18582474). These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53/p53 and apoptosis (PubMed:12499369, PubMed:12551934, PubMed:12607004). ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1 (PubMed:12499369, PubMed:12551934, PubMed:12607004). Required for chromosomal stability during mitosis by promoting recruitment of TOPBP1 to DNA double strand breaks (DSBs): TOPBP1 forms filamentous assemblies that bridge MDC1 and tether broken chromosomes during mitosis (PubMed:30898438). Required for the repair of DSBs via homologous recombination by promoting recruitment of NBN component of the MRN complex to DSBs (PubMed:18411307, PubMed:18582474, PubMed:18583988, PubMed:18678890).

Post-translational modifications

Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU) (PubMed:12607003, PubMed:12607004, PubMed:12607005). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2 (PubMed:12607003, PubMed:12607004, PubMed:12607005). Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint (PubMed:12607003, PubMed:12607004, PubMed:12607005). Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain (PubMed:22234877). Phosphorylated at Ser-168 and Ser-196 by CK2 in response to DNA damage during mitosis, promoting interaction with TOPBP1 (PubMed:30898438). Phosphorylated by CK2 in response to DNA damage, promoting interaction with NBN and recruitment of the MRN complex to DNA damage sites (PubMed:18411307, PubMed:18583988, PubMed:18678890).

Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation.

Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination.

Tissue Specificity

Highly expressed in testis.

Cellular localization

Alternative names

KIAA0170, NFBD1, MDC1, Mediator of DNA damage checkpoint protein 1, Nuclear factor with BRCT domains 1

swissprot:Q14676 entrezGene:9656 omim:607593 genbank:NP_055456