Identifying and defining the genome maintenance functions of SMARCAL1

Abstract

In this dissertation I identify and define SWI/SNF, matrix-associated, actin-dependent regulator of chromatin, A-like 1 (SMARCAL1) as a genome maintenance protein. First, I introduce a functional genomic screen designed to identify novel genome maintenance genes. This screen led to the identification of SMARCAL1 and is the foundation for my project, providing the preliminary evidence to support that SMARCAL1 functions to maintain genome integrity. Next, I investigate the specific genome maintenance activity of SMARCAL1 and find that localization of its enzymatic activity to stalled replication forks is required for genome integrity during DNA replication. Finally, I explore how phosphorylation of SMARCAL1 regulates its function. Importantly, mutations in SMARCAL1 cause the human disease Schmike immuno-osseous dysplasia (SIOD). The research presented herein suggests that the phenotypes of SIOD are, in part, due to defects in SMARCAL1 genome maintenance activity.