Insights into the regulation of the fanconi anemia FANCD2 protein
Fanconi anemia (FA) is a rare cancer susceptibility syndrome caused by biallelic mutation in any one of 15 genes. Together with BRCA1, the FA proteins act in concert in the FA-BRCA pathway to repair DNA damage and prevent cellular transformation. Central to this pathway is the monoubiquitination of the FANCD2 protein, a post-translational modification required for the retention of FANCD2 on chromatin at sites of DNA repair. Failure to monoubiquitinate FANCD2 renders cells hypersensitive to agents that induce DNA interstrand crosslinks (ICLs) and underscores the critical role of FANCD2 in DNA repair. Importantly, however, very little is known about the regulation of this protein. The goal of this dissertation is to enhance the current understanding of the regulation, structure and function of FANCD2. We have uncovered a novel role for the p21 cyclin-dependent kinase inhibitor in promoting FANCD2 monoubiquitination via the transcriptional repression of the USP1 gene. In the absence of p21, FANCD2 monoubiquitination is abrogated rendering cells hypersensitive to the clastogenic effects of the ICL-inducing agent mitomycin C (MMC). In addition, we have identified and characterized a ubiquitin-binding domain (UBD) in FANCD2. The FANCD2 UBD is required for the association of FANCD2 with its paralogue FANCI. Importantly, not only does mutation of the UBD impair the FANCD2-FANCI interaction, but it also renders FANCD2 susceptible to proteasome-mediated turnover. Taken together, we believe that our findings have considerably enhanced the scientific community's understanding of this important protein and will provide others with new avenues for investigation.^
Biology, Genetics|Biology, Cell|Biogeochemistry|Health Sciences, Oncology
Meghan Anne Rego,
"Insights into the regulation of the fanconi anemia FANCD2 protein"
Dissertations and Master's Theses (Campus Access).