mediator of DNA damage checkpoint protein 1 (nuclear factor with BRCT domains 1, MDC1, KIAA0170, NFBD1)

Function: 1) required for checkpoint mediated cell cycle arrest in response to DNA damage within both S phase & G2/M phase of the cell cycle 2) scaffold for the recruitment of DNA repair & signal transduction proteins to discrete foci of DNA damage marked by Ser-139 phosphorylation of histone H2AFX (putative) 3) required for downstream events subsequent to the recruitment of proteins to foci of DNA damage (see #2 above) - phosphorylation & activation of ATM, CHEK1/CHK1 & CHEK2/CHK2/CDS1 kinases - stabilization of TP53 - apoptosis 4) ATM & CHEK2 may also be activated independently (from #3 above) by a parallel pathway mediated by TP53BP1 5) interacts with several proteins involved in the DNA damage response, not all these interactions may be direct 6) interacts with H2AFX phosphorylated on Ser-139 7) interacts with the MRN complex 8) interacts with phosphorylated CHEK2/CHK2/CDS1 (ATM-mediated phosphorylation of Thr-68 within the FHA domain of CHEK2) 9) interacts constitutively with BRCA1-BARD1 complex, SMC1L1, TP53BP1 10) interactions with ATM & FANCD2 are diminished upon DNA damage 11) interacts with the PRKDC complex, may be required for PRKDC autophosphorylation, essential for DNA double strand break repair 12) phosphorylated on undefined residues upon exposure to ionizing radiation, ultraviolet radiation, & hydroxyurea 13) phosphorylation in response to ionizing radiation requires ATM, NBN, & possibly CHEK2 14) phosphorylated during the G2/M phase of cell cycle & during activation of the mitotic spindle checkpoint Structure: - contains 2 BRCT domains* - contains 1 FHA 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. Compartment: - nucleus, associated with chromatin - relocalizes to discrete nuclear foci following DNA damage - nuclear relocalization requires Ser-139 phosphorylation of H2AFX Alternative splicing: named isoforms=2 Expression: highly expressed in testis

General

nuclear protein phosphoprotein

Properties

SIZE: MW = 227 kD entity length = 2089 aa COMPARTMENT: cell nucleus MOTIF: interaction with CHEK2 {1-150} binding site SITE: 2-220 FOR-BINDING-OF: MRN complex MOTIF: forkhead-associated (FHA) domain {54-105} nuclear localization {145-568} MOTIF: Ser phosphorylation site {S168} Ser phosphorylation site {S329} Ser phosphorylation site {S964} Ser phosphorylation site {S988} Ser phosphorylation site {S995} proline-rich region SITE: 1034-1469 MOTIF: proline residue (SEVERAL) binding site SITE: 1148-1610 FOR-BINDING-OF: PRKDC complex MOTIF: Thr phosphorylation site {T1425} Thr phosphorylation site {T1461} nuclear localization {1698-2089} MOTIF: BRCA1 C-terminal (BRCT) motif SITE: 1892-1970 BRCA1 C-terminal (BRCT) motif SITE: 1991-2082

Database Correlations

OMIM 607593 UniProt Q14676 PFAM correlations Entrez Gene 9656 Kegg hsa:9656

References

UniProt :accession Q14676