Functional interaction between the Fanconi Anemia D2 protein and proliferating cell nuclear antigen (PCNA) via a conserved putative PCNA interaction motif.

Abstract	Fanconi Anemia (FA) is a rare recessive disease characterized by congenital abnormalities, bone marrow failure, and cancer susceptibility. The FA proteins and the familial breast cancer susceptibility gene products, BRCA1 and FANCD1/BRCA2, function cooperatively in the FA-BRCA pathway to repair damaged DNA and to prevent cellular transformation. Activation of this pathway occurs via the mono-ubiquitination of the FANCD2 protein, targeting it to nuclear foci where it co-localizes with FANCD1/BRCA2, RAD51, and PCNA. The regulation of the mono-ubiquitination of FANCD2, as well as its function in DNA repair remain poorly understood. In this study, we have further characterized the interaction between the FANCD2 and PCNA proteins. We have identified a highly conserved, putative FANCD2 PCNA interaction motif (PIP-box), and demonstrate that mutation of this motif disrupts FANCD2-PCNA binding and precludes the mono-ubiquitination of FANCD2. Consequently, the FANCD2 PIP-box mutant protein fails to correct the mitomycin C hypersensitivity of FA-D2 patient cells. Our results suggest that PCNA may function as a molecular platform to facilitate the mono-ubiquitination of FANCD2 and activation of the FA-BRCA pathway.
Authors	Niall G Howlett, Julie A Harney, Meghan A Rego, Frederick W Kolling 4th, Thomas W Glover
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 42 Pg. 28935-42 (Oct 16 2009) ISSN: 1083-351X [Electronic] United States
PMID	19704162 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Apoptosis Regulatory Proteins BLID protein, human BRCA2 Protein BRCA2 protein, human Fanconi Anemia Complementation Group D2 Protein Proliferating Cell Nuclear Antigen Ubiquitin Mitomycin
Topics	Animals Apoptosis Regulatory Proteins BRCA2 Protein (metabolism) COS Cells Cell Line, Tumor Chlorocebus aethiops DNA Damage DNA Repair Fanconi Anemia (metabolism) Fanconi Anemia Complementation Group D2 Protein (metabolism, physiology) Humans Mitomycin (chemistry) Mutagenesis, Site-Directed Mutation Proliferating Cell Nuclear Antigen (metabolism) Ubiquitin (chemistry)

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