Life Sci Alliance.: auth.: group van Leeuwen

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Life Sci Alliance. 2022 Jan 11;5(4):e202101153. doi: 10.26508/lsa.202101153. Print 2022 Apr.

Chl1 helicase controls replication fork progression by regulating dNTP pools

Amandine Batté 1, Sophie C van der Horst 1, Mireille Tittel-Elmer 1 2, Su Ming Sun 1, Sushma Sharma 3, Jolanda van Leeuwen 4, Andrei Chabes 3, Haico van Attikum 5

Abstract

Eukaryotic cells have evolved a replication stress response that helps to overcome stalled/collapsed replication forks and ensure proper DNA replication. The replication checkpoint protein Mrc1 plays important roles in these processes, although its functional interactions are not fully understood. Here, we show that MRC1 negatively interacts with CHL1, which encodes the helicase protein Chl1, suggesting distinct roles for these factors during the replication stress response. Indeed, whereas Mrc1 is known to facilitate the restart of stalled replication forks, we uncovered that Chl1 controls replication fork rate under replication stress conditions. Chl1 loss leads to increased RNR1 gene expression and dNTP levels at the onset of S phase likely without activating the DNA damage response. This in turn impairs the formation of RPA-coated ssDNA and subsequent checkpoint activation. Thus, the Chl1 helicase affects RPA-dependent checkpoint activation in response to replication fork arrest by ensuring proper intracellular dNTP levels, thereby controlling replication fork progression under replication stress conditions.