FANCD2: Fanconi Anemia and Cancer

Grete Dudek

March 27, 2007

DNA Damage Types & Fixes

Interstrand Cross Links

Double Strand BreaksHomologous recombinationNon-homologous end joiningWhich 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

BRCA1

start finish

Mutant Cross-Link Repair

Facts of Fanconi Anemia

12 complimentation groups, 11 clonedRadiation 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 mutationSmaller sizeMicropthalmia

(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 NHEJDNA damage leads to mutations in other

important genesMouse model isn’t good enough, but FA

is rare- one in 300,000 live birthsCisplatinPathway 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?