Function of ZFAND3 in the DNA Damage Response

The DNA-damage response (DDR) pathway maintains genomic integrity and prevents tumorigenesis. Human precancerous lesions exhibit high levels of DNA damage particularly during DNA replication. This observation has led to the idea that unresolved problems accrued during DNA replication can contribute to tumorigenesis. Mechanistically, such replication stress can arise when replication forks arrest at DNA lesions. Activation of the DDR leads to repair and restart of damaged replication forks using tumor-suppressor proteins such as BRCA1 (breast cancer 1). I hypothesize that multiple pathways are important in breast cancer to respond to the elevated levels of replication stress known to exist in both pre-cancerous lesions and tumors. I identified one putative new replication stress response protein (Zfand3) and characterized its regulation. We have also developed a new method termed iPOND (isolation of proteins on nascent DNA) to examine Zfand3 and other DDR protein dynamics and functions at moving and stalled replication forks in human cells. Our studies analyzed the temporal and spatial regulation of damaged fork repair. These findings provide insights into why defects in specific DDR pathways cause genome instability during DNA replication. These studies have implications for understanding breast cancer etiology. The original document contains color images.