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FANCD2: Fanconi Anemia and Cancer

FANCD2: Fanconi Anemia and Cancer. Grete Dudek March 27, 2007. DNA Damage Types & Fixes. Interstrand Cross Links Double Strand Breaks Homologous recombination Non-homologous end joining Which way?. Proposed Repair of Cross-Link. Proposed Repair of Cross-Link.

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FANCD2: Fanconi Anemia and Cancer

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  1. FANCD2: Fanconi Anemia and Cancer Grete Dudek March 27, 2007

  2. DNA Damage Types & Fixes • Interstrand Cross Links • Double Strand Breaks • Homologous recombination • Non-homologous end joining • Which way?

  3. Proposed Repair of Cross-Link

  4. Proposed Repair of Cross-Link

  5. Proposed Repair of Cross-Link • Problem 1: DNA lesion

  6. Proposed Repair of Cross-Link • Problem 1: DNA lesion • Problem 2: Double stranded break intermediate

  7. Proposed Repair of Cross-Link • Problem 1: DNA lesion • Problem 2: Double stranded break intermediate

  8. Proposed FA Pathway BRCA1 start finish

  9. Mutant Cross-Link Repair

  10. Facts of Fanconi Anemia • 12 complimentation groups, 11 cloned • Radiation vs. Mitomycin-C • The intermediate of an ICL is a double strand break. FANCD2 mutants may have defect in sensing the inter-strand cross link or processing it. • Increased amount of non-homologous end joining in FANCD2 mutants

  11. Knockout Mice • Null mutation • Smaller size • Micropthalmia (small eyes) • Germ cell problems- hypogonadism Day 1: normal in back

  12. Knockout Mice • Abnormal tubules in testes • Increased apoptosis in the spermatocytes • Ovaries from adult females were also abnormal

  13. Knockout Mice • Increased tumorigenesis in FancD2 -/- epithelial tissues • Slight increase in heterozygotes as well.

  14. Autosomal Recessive Symptoms Predisposition for acute myelogenous leukemia and solid tumors. Median survival age is approx 12 years. Fanconi Anemia

  15. Specific Mutations in Pathway • FA complex- needs all 8 functional proteins to monoubiquitinate FANCD2 • FANCD2- lysine to arginine mutation • BRCA2 (FANCD1) mutation

  16. FANCD2 in Cancer • FANCD2 mutations lead to NHEJ • DNA damage leads to mutations in other important genes • Mouse model isn’t good enough, but FA is rare- one in 300,000 live births • Cisplatin • Pathway can be inhibited to serve as a chemosensitizer in cancer therapy.

  17. Sources 1 D’Andrea AD. The Fanconi Road to cancer. Genes & Development. 2003;17:1933-1936. Houghtaling S, Granville L, Akkari Y, Torimaru Y, Olson S, Finegold M, et al. Heterozygousity for p53 (Trp53+/-) Accelerates Epithelial Tumor Growth in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice. Cancer Research. 2005;65(1):85-91. Houghtaling S, Timmers C, Noll M, Finegold MJ, Jones SN, Meyn MS, et al. Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice. Genes & Development. 2003;17:2021-2035. Kennedy RD, D’Andrea AD. The Fanconi Anemia/BRCA pathway: new faces in the crowd. Genes & Development. 2005;19:2925-2940. Kiato H, Yamamoto K, Matushita N, Ohzeki M, Ishiai M, Takata M. Functional Interplay between BRCA2/FANCD1 and FANCC in DNA Repair. Journal of Biological Chemistry. 2006;281(30):21312-21320.

  18. Sources 2 Mirchandani K, D’Andrea AD. The Fanconi anemia/BRCA pathway: A coordinator of cross-link repair. Experimental Cell Research. 2006;312:2647-2653. Offit K, Levran O, Mullaney B, Mah K, Nafa K, Batish SD, et al. Shared Genetic Suceptibility to Breast Cancer, Brain Tumors, and Fanconi Anemia. Journal of the National Cancer Institute. 2003;95(20):1548-1551. Park WH, Margossian S, Horwitz AA, Simons AM, D’Andrea AD, Parvin JD. Direct DNA Binding Activity of the Fanconi Anemia D2 Protein. 2005;280(25)23593-23598. Pejovic T, Yates JE, Liu HY, Hays LE, Akkari Y, Torimaru Y, et al. Cytogenetic Instability in Ovarian Epithelial Cells from Women at Risk of Ovarian Cancer. Cancer Research. 2006;66(18):9017-9025. Thompson LH, Hinz JM, Yamada NA, Jones NJ. How Fanconi Anemia Proteins Promote the Four Rs: Replication, Recombination, Repair, and Recovery. Wiley Interscience. 2005;45:128-142.

  19. Any Questions?

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