FANCD2& the Fanconi Anemia Tumor Suppressor Pathway

Shayna Purcell

Joo et al., 333 (6040): 312-316

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by

genomic instability

Moldovan and D’Andrea, Annu. Rev. Genet. 2009.43:224

Disruption of the FA pathway causes chromosomal breakages and

hypersensitivity to DNA interstrand crosslinks (ICLs)

Deans, Nature Reviews Cancer 11, 467-480 (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, 1128 - 1130 (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 1992. Web. 19 Mar. 2015.

"FA Fact Sheet." Fanconi Anemia Research Fund, Inc. 1 Feb. 2014. Web. 20 Mar. 2015.

Houghtaling, Scott. "Epithelial Cancer in Fanconi Anemia Complementation Group D2 (Fancd2) Knockout Mice." Genes & Development 17 (2003): 2021-035. Cold Spring Harbor Laboratory Press. Web. 18 Mar. 2015.

"How Is Fanconi Anemia Treated?" NIH National Heart, Lung and Blood Institute. U.S. Department of Health & Human Services, 1 Nov. 2011. Web. 26 Mar. 2015.

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): 895-910. ScienceDirect. Web. 22 Mar. 2015.

Moldovan, George-Lucian, and Alan D. D'Andrea. "How the Fanconi Anemia Pathway Guards the Genome." Annual Review of Genetics 43 (2009): 223-49. Annual Reviews. Web. 19 Mar. 2015.

Pickering, Anna et al. “Advances in the Understanding of the Fanconi Anemia Tumor Suppressor Pathway.” Cancer Biology & Therapy 14.12 (2013): 1089–1091. PMC. Web. 26 Mar. 2015.