Date of Award

2017

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 X-linked recessive disorder, characterized by congenital abnormalities, pediatric bone marrow failure and cancer susceptibility. FA is caused by biallelic mutation in any one of 22 different genes. The main functions of the FA-BRCA pathway is the resolution of interstrand crosslinks (ICLs) within the DNA. The main activating step of the pathway is the monoubiquitination of the proteins FANCD2 and FANCI. In the first chapter of this dissertation I discuss how methylation and acetylation affect chromatin architecture and activation of the pathway. In the second chapter I will discuss the effects of FANCD2 phosphorylation in a DNA damage-independent, cell cycle-dependent manner. We show that monoubiquitination of FANCD2 is blocked by phosphorylation and that this phosphorylation acts as a molecular switch to alter FANCD2 function.

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