Investigating Non-Canonical Roles of ATR and CHK1 Throughout the Cell Cycle

ABSTRACT

Chromosome Instability (CIN), which results from DNA damage in interphase and chromosome missegregation in mitosis, is considered to be a potent driver of cancer. To prevent CIN, cells harbor the DNA Damage Response (DDR) pathway, which is responsible for detecting and repairing damaged DNA. Because of their importance in preventing CIN, the core members of the DDR pathway such as Ataxia Telangiectasia and Rad3-related (ATR) and Checkpoint kinase 1 (CHK1) have been studied as promising targets in cancer therapy. However, clinical trials show that ATR and CHK1 inhibitors elicit adverse side effects with unknown reasons. Recent research suggests that one of the reasons for the unexpected side effects is that ATR and CHK1 are multifaceted proteins that are involved in multiple different pathways while the current clinical strategies only focus on their role in the DDR pathway. In this dissertation, we show that ATR and CHK1 have multiple roles throughout the cell cycle that is not limited to the DDR pathway in both promoting the rupture of micronucleus (MN) in interphase and faithful chromosome segregation during mitosis.