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 genetic disease that results on early onset bone marrow failure, congenital defects, and increased cancer susceptibility. It is caused by mutation in any one of twenty two genes, whose protein products work in conjunction as part of the FA-BRCA pathway, a DNA repair pathway that specifically repairs DNA interstrand crosslinks (ICLs). One of the key steps in pathway activation is the monoubiquitination of the FANCD2 protein. Upon pathway activation, FANCD2 is recruited to sites of DNA damage, where is interacts with downstream repair protiens to promote DNA repair via homologous recombination (HR). How FANCD2 recognizes DNA damage in condensed compact chromatin, however, has remained unknown. Here, we uncover a FANCD2 methyl-binding domain, which specifically binds for H4K20me2 in order to recruit FANCD2 to sites on DNA damage and promote homologous recombination, support cell survival and maintain genomic integrity.

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