Study of molecular pathogenesis of Fanconi anemia

• Project/Area Number: 14570963
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: YAMASHITA Takayuki The University of Tokyo, The Institute of Medical Science, Teaching Staff of Donation Laboratory, 医科学研究所, 寄付研究部門教員(常勤形態) (10166671)
• Co-Investigator(Kenkyū-buntansha): ODA Tsukasa The University of Tokyo, The Institute of Medical Science, Teaching Staff of Donation Laboratory, 医科学研究所, 寄付研究部門教員(常勤形態) (10323643)
• Project Period (FY): 2002 – 2003
• Project Status: Completed (Fiscal Year 2003)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: Fanconi anemia / DNA repair / ubiquitin ligase / protein interaction / nuclear transport / reversion / Fanconi貧血 / 骨髄不全 / 熱ショック蛋白 / 再生不良性貧血 / 骨髄異形成症候群 / 白血病 / ゲノム不安定性

Research Abstract

Fanconi anemia is an autosomal recessive disorder of hematopoiesis with at least 11 genetically different groups, characterized by cellular hypersensitivity to DNA cross-linkers and chromosome instability. To date, 8 genes have been identified. A multiprotein complex including these gene products, FANCAICJE/F/G/L is required for activation of FANCD2 into a monoubiquitinated form. This active form affects genomic instability in collaboration with BRCA1 and BRCA2IFANCD1. In this project, we studied functions of FANCA mutants with amino acid substitution in its N-terminal region including nuclear localization signal and FANCG-binding sites. Our results indicate that formation of a stable complex including FANCAICIE/FIGIL is not essential for FANCD2 activation. It seems that nuclear import of FANCA/L complex palys a central role in this pathway, and that FANCG negatively regulates nuclear import of FANCA. Furthermore, we identified Hsc7O as a FANCA-binding protein. A dominant-negative form of Hsc7O and 17-AAG, a specific inhibitor of Hsp9O, inhibited nuclear localization of FANCA, suggesting that a chaperone complex including Hsc7O is required for nuclear import of FANCA. We identified FANCA mutations in 27 Japanese FA patients and found novel molecular mechanisms of generation of large deletions in this gene. We found that long-term remission of bone marrow failurewas associated with myeloid lineage-selective expansion of cells with reversion in a patient. This case suggests the clinical usefulness of gene therapy.

Research Products

• [Publications] Yagasaki H, Yamashita T et al.: "Two common founder mutations of the Fanconi anemia group G gene FANCG/XRCC9 in the Japanese population."Hum Mutat. 21. 555 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hamanoue S, Yamashita T et al.: "Persistent hematopoiesis associated with lineage-selective mosaicism in Fanconi anemia"Blood. 102. 5059 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yagasaki H, Yamashita T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Hum Mutat. (印刷中). (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Oda T, Yamashita T et al.: "ABT1-associated protein (ABTAP), a novel nuclear protein conserved from yeast to mammals, represses transcriptional activation by ABT1."J Cell Biochem. (印刷中). (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yagasaki H, Yamashita T et al.: "Two common founder mutations of the Fanconi anemia group G gene FANCG/XRCC9 in the Japanese population."Hum Mutat. 21. 555 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hamanoue S, Yamashita T et al.: "Persistent hematopoiesis associated with lineage-selective mosaicism in Fanconi anemia"Blood. 102. 505a (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yagasaki H, Yamashita T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Hum Mutat. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Oda T, Yamashita T et al.: "ABT1-associated protein (ABTAP), a novel nuclear protein conserved from yeast to mammals, repressestranscriptional activation by ABT1."J Cell Biochem. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yagasaki H, Yamashita T et al.: "Two common founder mutations of the Fanconi anemia group G gene FANCG/XRCC9 in the Japanese population"Hum Mutat. 21. 555 (2003)
• [Publications] Hamanoue S, Yamashita T et al.: "Persistent hematopoiesis associated with lineage-selective mosaicism in Fanconi anemia"Blood. 102. 505a (2003)
• [Publications] Yagasaki H, Yamashita T et al.: "Identification and characterization of novel mutations of the major Fanconi anemia gene FANCA in the Japanese population."Hum Mutat. (印刷中). (2004)
• [Publications] Oda T, Yamashita T et al.: "ABT1-associated protein(ABTAP), a novel nuclear protein conserved from yeast to mammals, represses transcriptional activation by ABT1."J Cell Biochem. (印刷中). (2004)
• [Publications] Adachi D, Oda T, Yamashita T, et al.: "Heterogenous activation of the Fanconi anemia pathway by patient-derived FANCA mutants"Hum. Mol. Genet.. 11. 3125-2002 (2002)
• [Publications] Yagasaki H, Oda T, Yamashita T, et al.: "Two common founder mutations of the Fanconi anemia group G gene FANCG/XRCC in the Japanese population"Hum Mutat. (印刷中). (2003)