DNA-crosslinking agents such as cisplatin, carboplatin, cyclophosphamide, mitomycin C and melphalan are widely-used drugs for treatment of cancers including leukemia, lymphoma, and myeloma. Resistance to these drugs is a major problem for effective cancer therapy. Fanconi anemia is a genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and hypersensitivity to DNA-crosslinking agents. Fanconi anemia proteins and breast cancer susceptibility proteins (BRCA1 and BRCA2) cooperate in a pathway (the Fanconi anemia-BRCA pathway), which controls DNA repair. This pathway is required for cellular resistance to DNA-crosslinking agents. Inhibition of this pathway is therefore an attractive therapeutic strategy to overcome DNA-crosslinker resistance. Key proteins in the pathway, such as FANCD2 and RAD51, accumulate at sites of DNA damage and repair, form nuclear foci and regulate DNA repair. Formation of these nuclear foci is a good marker of the integrity of the pathway. MicroRNAs are non-coding RNA molecules that post-transcriptionally regulate gene expression. MicroRNAs are involved in biological processes such as cell proliferation, differentiation and apoptosis, and are deregulated in cancer. However, regulation of the Fanconi anemia-BRCA pathway by microRNAs has not been investigated. Through screening of microRNA mimics &inhibitors library, we have identified several microRNA mimics and inhibitors which inhibit formation of FANCD2 and RAD51 foci. Therefore, we hypothesize that the Fanconi anemia-BRCA pathway is regulated by microRNAs. Interestingly, some of the miRNAs we identified are known to be deregulated in a subset of human cancers. The goals of our research are 1) to identify microRNAs regulating the Fanconi anemia-BRCA pathway, 2) to elucidate whether the microRNAs affect cellular sensitivity to DNA-crosslinkers and efficiency of DNA repair, and 3) to elucidate the mechanism(s) of regulation of the pathway by the microRNAs. Our study will lead to the discovery of novel factors (microRNAs and their target genes) involved in the Fanconi anemia-BRCA pathway. These factors may be novel cancer/leukemia susceptibility genes or Fanconi anemia genes, as are other factors in the pathway. Deregulation of these factors may determine chemosensitivity. Thus, this project could have an impact on the basic understanding of Fanconi anemia, cancer/leukemia susceptibility and chemosensitivity of cancer cells.
Our studies are intended to clarify how DNA repair is regulated by microRNAs. Our studies will provide basic understanding of a blood disease called Fanconi Anemia and also lead to a discovery of ways to make cancer chemotherapy more effective.
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