Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation.
Although it is well established that inheritance of mutations in the Brca1 gene significantly increases the chances of developing breast or ovarian cancers, the mechanisms underlying this specific tumor susceptibility remain to be clarified. It is clear that one of the roles of the Brca1 protein is to facilitate cellular responses to DNA damage. We recently reported that Brca1 function is required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. We also found that mutation of serine 1423 in Brca1, a target of Atm phosphorylation, abrogates the G2-M checkpoint but not the ionizing irradiation-induced S-phase checkpoint. Here we demonstrate that mutation of serine 1387 in Brca1, another target of Atm phosphorylation, conversely abrogates the radiation-induced S-phase arrest but does not affect the G2-M checkpoint. Thus, these two posttranslational modifications of Brca1 have two distinct functional roles in the protein. In addition, although mutation of this site abrogates the ionizing irradiation-induced S-phase arrest, it does not adversely affect cell survival after irradiation. This demonstrates that loss of this checkpoint function by itself does not affect cell survival and suggests that some other function of Brca1 alters cell survival after DNA damage.
Xu
Bo
B
Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
O'Donnell
Anne H
AH
Kim
Seong-Tae
ST
Kastan
Michael B
MB
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D004249:DNA Damage; D004268:DNA-Binding Proteins; D016195:G2 Phase / Q000502:physiology / Q000528:radiation effects; D019398:Genes, BRCA1; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D016196:S Phase / Q000502:physiology* / Q000528:radiation effects; D012694:Serine / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D012694:Serine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases