MicroRNAs Regulating The Fanconi Anemia-BRCA Pathway

Summary

Principal Investigator: Toshiyasu Taniguchi
Abstract: DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.
Funding Period: 2008-09-19 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition
    Yemin Wang
    Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
    Cancer Res 72:4037-46. 2012
  2. pmc MicroRNAs and DNA damage response: implications for cancer therapy
    Yemin Wang
    Howard Hughes Medical Institute, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
    Cell Cycle 12:32-42. 2013
  3. pmc Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity
    Jen Wei Huang
    Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1 015, Seattle, WA 98109 1024
    Mol Cancer Res 11:1564-73. 2013
  4. pmc p53 is positively regulated by miR-542-3p
    Yemin Wang
    Authors Affiliations Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center Molecular and Cellular Biology Program, University of Washington, Seattle, Washington and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, CanadaAuthors Affiliations Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center Molecular and Cellular Biology Program, University of Washington, Seattle, Washington and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada
    Cancer Res 74:3218-27. 2014
  5. pmc MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression
    Yemin Wang
    Howard Hughes Medical Institute, Division of Human Biology, University of Washington, Seattle, Washington, USA
    Mol Cancer Res 9:1100-11. 2011

Detail Information

Publications5

  1. pmc MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition
    Yemin Wang
    Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
    Cancer Res 72:4037-46. 2012
    ..As a therapeutic candidate, miR-96 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage...
  2. pmc MicroRNAs and DNA damage response: implications for cancer therapy
    Yemin Wang
    Howard Hughes Medical Institute, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
    Cell Cycle 12:32-42. 2013
    ..In this review, we summarize recent findings related to the emerging roles of miRNAs in regulating DDR and DNA repair and discuss their potential in cancer therapy...
  3. pmc Systematic screen identifies miRNAs that target RAD51 and RAD51D to enhance chemosensitivity
    Jen Wei Huang
    Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, C1 015, Seattle, WA 98109 1024
    Mol Cancer Res 11:1564-73. 2013
    ..Taken together, these data show that miR-103 and miR-107 overexpression promotes genomic instability and may be used therapeutically to chemosensitize tumors...
  4. pmc p53 is positively regulated by miR-542-3p
    Yemin Wang
    Authors Affiliations Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center Molecular and Cellular Biology Program, University of Washington, Seattle, Washington and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, CanadaAuthors Affiliations Divisions of Human Biology and Public Health Sciences, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center Molecular and Cellular Biology Program, University of Washington, Seattle, Washington and Department of Pathology and Laboratory Medicine, Center for Translational and Applied Genomics, British Columbia Cancer Agency, University of British Columbia, Vancouver BC, Canada
    Cancer Res 74:3218-27. 2014
    ..Our results define miR-542-3p as an important new positive regulator of p53 with potential applications in cancer treatment...
  5. pmc MicroRNA-138 modulates DNA damage response by repressing histone H2AX expression
    Yemin Wang
    Howard Hughes Medical Institute, Division of Human Biology, University of Washington, Seattle, Washington, USA
    Mol Cancer Res 9:1100-11. 2011
    ..Our study suggests that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy with DNA-damaging agents...