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bioRxiv · 10.64898/2026.05.14.725212

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

Schauer, G. D.·Argueso, J. L.·Stewart, J. A.·Lawson, V. M.·Brady, R. E.·Timmerman, A. J.
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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.

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Schauer, G. D., Argueso, J. L., Stewart, J. A., Lawson, V. M., Brady, R. E., Timmerman, A. J.. 2026-05-16. Mechanical tuning of replication stress tolerance and genomic stability through the checkpoint mediator Mrc1. https://doi.org/10.64898/2026.05.14.725212

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