Decision making at protected replication forks

The process of DNA replication is central to life. Several proteins encoded by genes important to cancer-predisposition syndromes and human development are essential when replication forks stall, preventing DNA nucleases from degrading the paused fork. The process suppresses genome instability and may be relevant to cancer therapy by determining particular therapeutic vulnerabilities and therapy resistances. However, the role, regulation and impact of replication fork protection is poorly understood, and we currently lack the knowledge of where the opportunities for improved human health in this process may lie. Using an integrated approach, we aim to address where and in response to what replication fork protection is most needed, how stalled protected and unprotected forks signal to recovery mechanisms, and how chromatin is regulated to promote recovery. We will reveal the molecular basis of decisions at protected and unprotected replication forks to define the opportunities for improved human health.