title: BRCA1 contributes to cell cycle arrest and chemoresistance in response to the anticancer agent irofulven.
abstract: Tumor suppressor gene BRCA1 is frequently mutated in familial breast and ovarian cancer. BRCA1 plays pivotal roles in maintaining genomic stability by interacting with numerous proteins in cell cycle control and DNA repair. Irofulven (6-hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is one of a new class of anticancer agents that are analogs of mushroom-derived illudin toxins. Preclinical studies and clinical trials have demonstrated that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. We demonstrated previously that irofulven activates ATM and its targets, NBS1, SMC1, CHK2, and p53. In this study, we hypothesize that irofulven induces DNA double-strand breaks and that BRCA1 may affect chemosensitivity by controlling cell cycle checkpoints, DNA repair, and genomic stability in response to irofulven treatment. We observed that irofulven induces the formation of chromosome breaks and radials and the activation and foci formation of gamma-H2AX, BRCA1, and RAD51. We also provided evidence that irofulven induces the generation of DNA double-strand breaks. By using BRCA1-deficient or -proficient cells, we demonstrated that in response to irofulven, BRCA1 contributes to the control of S and G(2)/M cell cycle arrest and is critical for repairing DNA double-strand breaks and for RAD51-dependent homologous recombination. Furthermore, we found that BRCA1 deficiency results in increased chromosome damage and chemosensitivity after irofulven treatment.
authors.affiliation: Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506-9300, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Jamie
authors.initials: J
authors.lastname: Senft
authors.forename: Yutian
authors.initials: Y
authors.lastname: Wang
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Konat
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Wenger
authors.forename: Eddie
authors.initials: E
authors.lastname: Reed
authors.forename: Weixin
authors.initials: W
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000187:drug effects / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D019457:Chromosome Breakage; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004351:Drug Resistance / Q000187:drug effects*; D042822:Genomic Instability; D006801:Humans; D051135:Rad51 Recombinase / Q000187:drug effects; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D012717:Sesquiterpenes; C102714:irofulven; D051135:Rad51 Recombinase