Novel Aspects to the Role of Rad9A During the DNA Damage Response

Abstract

The human Rad9A checkpoint protein is required for genomic stability and proper execution of the DNA damage checkpoint. Previous work has shown Rad9A to be the key member of a heterotrimeric toroidal structure known as the 911 complex, along with Hus1A and Rad1, which is similar in structure to PCNA. Recent literature suggests Rad9A is a novel oncogene, found to be upregulated in a number of cancers and high mRNA levels are thought to have a protective effect on tumour growth. This thesis describes two novel functions for the Rad9A protein. The first is as a facilitator for the nuclear translocation of the Claspin adaptor protein, required for successful Chk1-mediated checkpoint activation. The second is as part of a novel nuclear structure containing important members of the homologous recombination DNA repair pathway. Work described herein also confirms the existence of a Rad9A paralogue, Rad9B, that partially rescues defects associated with Rad9A-deficiency and is expressed in both tumour and undifferentiated embryonic stem cell lines. This work discusses these findings in the context of current literature and provides future experiments to continue investigations into the function of this vital checkpoint protein.