Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Biological and Environmental Sciences

Specialization

Cell and Molecular Biology (CMB)

Department

Cell & Molecular Biology

First Advisor

Niall Howlett

Abstract

Fanconi anemia (FA) is a rare autosomal and X-linked recessive disorder, characterized by congenital abnormalities, pediatric bone marrow failure and cancer susceptibility. FA is caused by biallelic mutations in any one of 16 genes. The FA proteins function cooperatively in the FA-BRCA pathway to repair DNA interstrand crosslinks (ICLs). The monoubiquitination of FANCD2 and FANCI is a central step in the activation of the FA-BRCA pathway and is required for targeting these proteins to chromatin. Despite their critical role in ICL repair, very little is known about the structure, function, and regulation of the FANCD2 and FANCI proteins, or how they are targeted to the nucleus and chromatin. The goal of this dissertation is to study the mechanisms and regulation of FANCD2. Through this research, we have uncovered a nuclear localization signal (NLS) in FANCD2. Mutation of this NLS region impairs FANCD2 and FANCI monoubiquitination and inhibits the recruitment of FANCD2 and FANCI to chromatin. In addition, we have identified a putative CDK phosphorylation site cluster in FANCD2. Taken together, we believe these findings have enhanced our understanding of this important DNA repair protein and will allow for further investigation of this rare cancer susceptibility syndrome.

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