title: Fanconi anemia D2 protein confers chemoresistance in response to the anticancer agent, irofulven.
abstract: The Fanconi anemia-BRCA pathway of genes are frequently mutated or epigenetically repressed in human cancer. The proteins of this pathway play pivotal roles in DNA damage signaling and repair. Irofulven is one of a new class of anticancer agents that are analogues of mushroom-derived illudin toxins. Preclinical studies and clinical trials have shown that irofulven is effective against several tumor cell types. The exact nature of irofulven-induced DNA damage is not completely understood. Previously, we have shown 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 FANCD2 may play an important role in modulating cellular responses and chemosensitivity in response to irofulven treatment. By using cells that are proficient or deficient for FANCD2, ATR, or ATM, we showed that irofulven induces FANCD2 monoubiquitination and nuclear foci formation. ATR is important in mediating irofulven-induced FANCD2 monoubiquitination. Furthermore, we showed that FANCD2 plays a critical role in maintaining chromosome integrity and modulating chemosensitivity in response to irofulven-induced DNA damage. Therefore, this study suggests that it might be clinically significant to target irofulven therapy to cancers defective for proteins of the Fanconi anemia-BRCA pathway.
authors.affiliation: Mary Babb Randolph Cancer Center, West Virginia University, 1835 Health Sciences South, P.O. Box 9300, Morgantown, WV 26506, USA. wwang@hsc.wvu.edu
authors.forename: Yutian
authors.initials: Y
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Wiltshire
authors.forename: Jamie
authors.initials: J
authors.lastname: Senft
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: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002877:Chromosomes, Human / Q000187:drug effects / Q000502:physiology; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014162:Transfection; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018797:Cell Cycle Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; D012717:Sesquiterpenes; D014452:Ubiquitins; C102714:irofulven; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases