Rif1-dependent regulation of DNA replication in Drosophila

Abstract

Successful duplication of the genome requires the accurate replication of billions of base pairs of DNA within a relatively short time frame. Regulation of DNA replication and copy number are necessary to promote genome stability and maintain cell and tissue function. These regulations, however, must also be flexible as replication kinetics can change through development and differentiation. DNA replication is regulated temporally in a process known as replication timing (RT). Rif1 is a key regulator of RT and has a critical function in copy number control in polyploid cells of Drosophila. In this dissertation, I have explored the relative contributions that cell lineage, cell cycle, and replication initiation regulators have on RT, by utilizing the powerful developmental systems available in Drosophila melanogaster. I have also looked into the contributions of SUUR and Rif1 on Underreplication (UR) and RT by applying a computational approach to measure RT in Drosophila polyploid cells. Together the work supports a model in which the RT program is primarily driven by cell lineage and is further refined by Rif1/PP1 to ultimately generate tissue-specific RT programs. Additionally, it reveals that SUUR and Rif1 have differential roles in controlling UR and RT and provides new insight into the interconnections of these processes. Many questions, however, remain about the intricacies of Rif1 function. Hence, I have provided a review of the current models for Rif1 activity with the goal of trying to understand how Rif1 regulates the DNA replication dynamics.