Mediator of DNA damage checkpoint protein 1 regulates BRCA1 localization and phosphorylation in DNA damage checkpoint control.
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.
Lou
Zhenkun
Z
Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Chini
Claudia Christiano Silva
CC
Minter-Dykhouse
Katherine
K
Chen
Junjie
J
D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000096:biosynthesis* / Q000378:metabolism*; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D015536:Down-Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D005982:Glutathione Transferase; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases