Mechanical tuning of replication stress tolerance and genomic stability through the checkpoint mediator Mrc1

Abstract

Mrc1 is a replication fork component that mediates communication between the replication checkpoint and fork progression. Here, we find that Mrc1 forms a dynamic mechanical linkage between CMG helicase and DNA Polymerase {varepsilon} that balances fork stability and flexibility. In its coupled state, Mrc1 bridges CMG helicase and the Pol2 C-terminal domain of Polymerase {varepsilon} to maintain helicase-polymerase coordination, promoting tolerance to replication stress but constraining fork remodeling. Upon checkpoint activation, Mec1/Rad53-dependent phosphorylation of Mrc1 shifts this equilibrium toward a loosened state, reducing coupling and enabling fork flexibility and lower mutation rate at the cost of reduced stress resistance.