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

Proposed Repair of Cross-Link Problem 1: DNA lesion

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

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

Proposed FA Pathway start finish FA complex activated through Bloom or ATR, it isn’t important which one- say various proposed pathways. BRCA1 start finish

Mutant Cross-Link Repair

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

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

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

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

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

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

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.

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.

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.

Any Questions?