title: Turnover of BRCA1 involves in radiation-induced apoptosis.
abstract: BACKGROUND
  Germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) increase the susceptibility to tumorigenesis. The function of BRCA1 is to regulate critical cellular processes, including cell cycle progression, genomic integrity, and apoptosis. Studies on the regulation of BRCA1 have focused intensely on transcription and phosphorylation mechanisms. Proteolytic regulation of BRCA1 in response to stress signaling remains largely unknown. The manuscript identified a novel mechanism by which BRCA1 is regulated by the ubiquitin-dependent degradation in response to ionization.
  
  
  RESULTS
  Here, we report that severe ionization triggers rapid degradation of BRCA1, which in turn results in the activation of apoptosis. Ionization-induced BRCA1 turnover is mediated via an ubiquitin-proteasomal pathway. The stabilization of BRCA1 significantly delays the onset of ionization-induced apoptosis. We have mapped the essential region on BRCA1, which mediates its proteolysis in response to ionization. Moreover, we have demonstrated that BRCA1 protein is most sensitive to degradation when ionization occurs during G2/M and S phase.
  
  
  CONCLUSIONS
  Our results suggest that ubiquitin-proteasome plays an important role in regulating BRCA1 during genotoxic stress. Proteolytic regulation of BRCA1 involves in ionization-induced apoptosis.
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Weijun
authors.initials: W
authors.lastname: Liu
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zong
authors.forename: George
authors.initials: G
authors.lastname: Wu
authors.forename: Takeo
authors.initials: T
authors.lastname: Fujita
authors.forename: Wenqi
authors.initials: W
authors.lastname: Li
authors.forename: Judy
authors.initials: J
authors.lastname: Wu
authors.forename: Yong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D017209:Apoptosis; D019313:BRCA1 Protein / Q000096:biosynthesis*; D002453:Cell Cycle; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D019398:Genes, BRCA1; D016678:Genome / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D007477:Ions; D051379:Mice; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D007477:Ions; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex