Executive Summary : | DNA replication forks are constantly challenged by various factors, leading to slowdown or stalling, which poses a significant threat to genome duplication. Defects in these mechanisms can result in mutation accumulation and genome instability, a leading cause of human diseases like cancer. Stalled forks can undergo remodeling to generate reversed fork structures, which prevent ssDNA accumulation, repair damaged template DNA, and facilitate restart. However, reversed forks are susceptible to degradation by nucleases, leading to DSBs and chromosomal rearrangements. The role of BRCA1, BRCA2, RAD51, and RAD51 paralogs in human liver (HR) has been well established, but recent studies have demonstrated HR independent functions in fork protection. BRCA2 promotes stable RAD51 nucleofilaments onto nascent strands and prevents degradation of reversed forks by MRE11 nuclease. BRCA1, FANCD2, and RAD51 paralogs also participate in fork stabilization. SNF2 family chromatin remodelers, such as SMARCAL1, ZRANB3, and HLTF, are ATPase-dependent DNA translocases that promote fork remodeling in an ATPase-dependent fashion. Unregulated fork remodeling can lead to chromosomal rearrangements and genome instability. BRCA2 has been reported to control remodeling of stalled forks by SMARCAL1. FANCM helicase catalyzes remodeling of stalled fork structures, and preliminary data with iPOND shows that FANCM and RAD51C localize to stalled fork sites, and RAD51C and FANCM interact. The proposed objectives aim to investigate the role of RAD51C in controlling FANCM mediated fork remodeling and facilitating replication restart. |