Date of Award

2020

Degree Type

Thesis

Degree Name

Master of Science in Biological and Environmental Sciences (MSBES)

Specialization

Cell & Molecular Biology

Department

Cell & Molecular Biology

First Advisor

Niall G. Howlett

Abstract

Fanconi anemia (FA) is a rare genetic disease characterized by increased risk for bone marrow failure and cancer. The FA proteins function together to repair damaged DNA. A central step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins under conditions of cellular stress and during Sphase of the cell cycle. The regulatory mechanisms governing S-phase monoubiquitination, in particular, are poorly understood. In this study, we have identified a CDK regulatory phospho-site (S592) proximal to the site of FANCD2 monoubiquitination. FANCD2 S592 phosphorylation during S-phase was detected by LC-MS/MS and by immunoblotting with a S592 phospho-specific antibody. Mutation of S592 disrupts S-phase and DNA damage-inducible monoubiquitination. In addition, FA-D2 (FANCD2-/-) patient cells expressing S592 mutants display reduced proliferation under conditions of replication stress and increased mitotic aberrations, including nucleoplasmic bridges and multinucleated cells. Our findings describe a novel cell cycle-specific regulatory mechanism for the FANCD2 protein.

Available for download on Friday, August 13, 2021

Share

COinS