FANCD2and its role in FA and other Cancers

Christina Miller

Fanconi Anemia is a congenital cancer predisposition syndrome that causes

chromosomal instability

Bone marrow failure Sensitivity to cross-linking

agents

FANCD2 is expressed in tissues where proliferation occurs

http://dx.doi.org.libproxy.lib.unc.edu/10.1016/S1097-2765(01)00172-1

FANCD2 is regulated by post Translational Modification

Monoubiquitinated on Lys-561o Necessary for binding to

chromatin

Phosphorylated by ATM or ATR on Ser-222

http://www.scills.ac.uk/arno-alpi-research.shtml

http://dx.doi.org/10.1016/j.mrfmmm.2005.05.010

Interstrand Cross-links are covalent bonds that link DNA strands and block

replication

Frontiers in Bioscience 9, 421-437, January 1, 2004

FANCD2 is necessary for replication-dependent

ICL repair

https://walter.hms.harvard.edu/node/11

Nature Reviews Cancer 3, 23-34 (January 2003)

FANCD2 is also active in S Phase arrest pathway

Nature Reviews Cancer 3, 23-34 (January 2003)http://dx.doi.org/10.1016/j.dnarep.2004.04.005

FANCD2-/- mice show phenotypes similar to those

of FA patients

FANCD2-/- mutant eye one day after birth

Wild type eye one day after birth

Wild type and FANCD2-/- mutant one day after birth

Genes Dev. 2003 August 15; 17(16): 2021–2035.

Reduced FANCD2 expression is correlated with decreased survival of breast

cancer patients

Am J Pathol. 2010 June; 176(6): 2935–2947.

References Dronkert MLG, Kanaar R. Repair of DNA interstrand cross-links. Mutat Res /DNA

Repair. 2001 9/4;486(4):217-47. Grompe M, D'Andrea A. Fanconi anemia and DNA repair. Hum Mol

Genet. 2001;10:2253. Hölzel M, van Diest PJ, Bier P, Wallisch M, Hoatlin ME, Joenje H, et al. FANCD2 protein

is expressed in proliferating cells of human tissues that are cancer‐prone in fanconi anaemia. The Journal of Pathology. 2003;201(2):198-203.

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(16):2021-35.

Rudland PS, Platt-Higgins AM, Davies LM, et al. Significance of the Fanconi anemia FANCD2 protein in sporadic and metastatic human breast cancer. American Journal of Pathology.2010;176(6):2935–2947.

Shukla P, Ghosh K, Vundinti BR. Current and emerging therapeutic strategies for fanconi anemia. The HUGO Journal. 2012;6(1):1-8.

Venkitaraman AR. Tracing the network connecting BRCA and fanconi anaemia proteins. Nature reviews. Cancer. 2004;4(4):266-76.

Wang X, D’Andrea AD. The interplay of fanconi anemia proteins in the DNA damage response. DNA Repair. 2004 0;3(8–9):1063-9.