FANCD2: Fanconi Anemia and Cancer
description
Transcript of FANCD2: Fanconi Anemia and Cancer
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?