Mediator of DNA Damage Checkpoint Protein 1 Regulates BRCA1 Localization and Phosphorylation in DNA Damage Checkpoint Control

Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2003; 278(16):13599-602. DOI: 10.1074/jbc.C300060200
Source: PubMed

ABSTRACT BRCA1 is a tumor suppressor involved in DNA repair and damage-induced checkpoint controls. In response to DNA damage, BRCA1 relocalizes to nuclear foci at the sites of DNA lesions. However, little is known about the regulation of BRCA1 relocalization following DNA damage. Here we show that mediator of DNA damage checkpoint protein 1 (MDC1), previously named NFBD1 or Kiaa0170, is a proximate mediator of DNA damage responses that regulates BRCA1 function. MDC1 regulates ataxia-telangiectasia-mutated (ATM)-dependent phosphorylation events at the site of DNA damage. Importantly down-regulation of MDC1 abolishes the relocalization and hyperphosphorylation of BRCA1 following DNA damage, which coincides with defective G(2)/M checkpoint control in response to DNA damage. Taken together these data suggest that MDC1 regulates BRCA1 function in DNA damage checkpoint control.

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    • "DSBs usually result from insults such as X-or gamma rays or topoisomerase poisons, or simply arise when a replication fork encounters damaged DNA (Hartlerode & Scully, 2009). DSB repair takes place in vivo within defined foci characterized by a distinctive histone phosphorylation (γ‐H2AX), accumulation of autophosphorylated DNA‐PKcs and recruitment of repair and signaling proteins, including 53BP1, NFBD1/MDC1 and the chromatin‐bound form of the MRE11/RAD50/NBS1 complex (Chan et al., 2002a; Lou et al., 2003; Mirzoeva & Petrini, 2001; Paull et al., 2000; Schultz et al., 2000; Shang et al., 2003). Two mechanisms have evolved to remediate this type of damage: non-homologous end joining (NHEJ) and homologous recombination (HR) (Hartlerode & Scully, 2009). "
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