FANCD2 & the Fanconi Anemia Tumor Suppressor Pathway Shayna Purcell Joo et al., 333 (6040):

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by genomic instability Moldovan and D’Andrea, Annu. Rev. Genet :224

Disruption of the FA pathway causes chromosomal breakages and hypersensitivity to DNA interstrand crosslinks (ICLs) Deans, Nature Reviews Cancer 11, (July 2011) Chang, BMC Medical Genomics. 2014;7:24

Clinical features of the disorder include: developmental defects, early-onset bone marrow failure & cancer predisposition Fanconi Anemia: Guidelines for Diagnosis and Management (2008)Fanconi Anemia Research Fund, Inc.

Following DNA damage, ATR activates the FA core complex; FANCD2-I is ubiquitinated and localized to chromatin foci Wang, Nature Structural & Molecular Biology 15, (2008)

Ghosal and Chen, Translational Cancer Research, Vol 2, No 3 (June 2013) FANCD2 ubiquitination initiates DNA repair through Nucleotide Excision Repair, Translesion Synthesis, and Homologous Recombination

In mice: Fancd2 -null mutant phenotype includes microphtalmia, perinatal lethality, and tumor development Houghtaling, Genes & Development, 17:2021–2035 © 2003

In humans: splicing mutations of FANCD2 predominate, leading to residual FANCD2 protein in cells Kalb, the American Journal of Human Genetics, Vol. 80, Issue 5, p895–910, May 2007

Long-term treatments of FA: blood and marrow stem cell transplant, androgen therapy, synthetic growth factors, or gene therapy MacMillan, November 15, 2013; Blood: 122 (21)

References "Fanconi Anemia, Complementation Group D2; FANCD2." Online Mendelian Inheritance in Man. Johns Hopkins University, 26 June Web. 19 Mar "FA Fact Sheet." Fanconi Anemia Research Fund, Inc. 1 Feb Web. 20 Mar Houghtaling, Scott. "Epithelial Cancer in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice." Genes & Development 17 (2003): Cold Spring Harbor Laboratory Press. Web. 18 Mar "How Is Fanconi Anemia Treated?" NIH National Heart, Lung and Blood Institute. U.S. Department of Health & Human Services, 1 Nov Web. 26 Mar Kalb, Reinhard. "Hypomorphic Mutations in the Gene Encoding a Key Fanconi Anemia Protein, FANCD2, Sustain a Significant Group of FA-D2 Patients With Severe Phenotype." American Journal of Human Genetics 80.5 (2007): ScienceDirect. Web. 22 Mar Moldovan, George-Lucian, and Alan D. D'Andrea. "How the Fanconi Anemia Pathway Guards the Genome." Annual Review of Genetics 43 (2009): Annual Reviews. Web. 19 Mar Pickering, Anna et al. “Advances in the Understanding of the Fanconi Anemia Tumor Suppressor Pathway.” Cancer Biology & Therapy (2013): 1089–1091. PMC. Web. 26 Mar