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 start finish
FA complex activated through Bloom or ATR, it isn’t important which one- say various proposed pathways.
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. Fanconi Anemia Autosomal Recessive Symptoms
Predisposition for acute myelogenous leukemia and solid tumors.
Median survival age is approx 12 years.

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:
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:
Kennedy RD, D’Andrea AD. The Fanconi Anemia/BRCA pathway: new faces in the crowd. Genes & Development ;19:
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):

18. Sources 2
Mirchandani K, D’Andrea AD. The Fanconi anemia/BRCA pathway: A coordinator of cross-link repair. Experimental Cell Research. 2006;312:
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 ;95(20):
Park WH, Margossian S, Horwitz AA, Simons AM, D’Andrea AD, Parvin JD. Direct DNA Binding Activity of the Fanconi Anemia D2 Protein ;280(25)
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):
Thompson LH, Hinz JM, Yamada NA, Jones NJ. How Fanconi Anemia Proteins Promote the Four Rs: Replication, Recombination, Repair, and Recovery. Wiley Interscience ;45:

19. Any Questions?