Mrc1 and Rad9 cooperate to regulate initiation and elongation of DNA replication in response to DNA damage

The EMBO Journal
Julien BacalPhilippe Pasero

Abstract

The S-phase checkpoint maintains the integrity of the genome in response to DNA replication stress. In budding yeast, this pathway is initiated by Mec1 and is amplified through the activation of Rad53 by two checkpoint mediators: Mrc1 promotes Rad53 activation at stalled forks, and Rad9 is a general mediator of the DNA damage response. Here, we have investigated the interplay between Mrc1 and Rad9 in response to DNA damage and found that they control DNA replication through two distinct but complementary mechanisms. Mrc1 rapidly activates Rad53 at stalled forks and represses late-firing origins but is unable to maintain this repression over time. Rad9 takes over Mrc1 to maintain a continuous checkpoint signaling. Importantly, the Rad9-mediated activation of Rad53 slows down fork progression, supporting the view that the S-phase checkpoint controls both the initiation and the elongation of DNA replication in response to DNA damage. Together, these data indicate that Mrc1 and Rad9 play distinct functions that are important to ensure an optimal completion of S phase under replication stress conditions.

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Citations

Nov 24, 2018·Current Genetics·María Moriel-CarreteroBenjamin Pardo
Aug 9, 2019·The EMBO Journal·Michael Charles LanzMarcus Bustamante Smolka
Jan 16, 2020·Molecular Biology of the Cell·Jinrong FengMalcolm Whiteway
Dec 7, 2018·Genes·Félix Prado
Sep 12, 2020·Nature Communications·Lisa PrendergastManolis Papamichos-Chronakis
Aug 10, 2020·Nature Communications·Alexy PromonetPhilippe Pasero
Nov 18, 2019·Current Opinion in Chemical Biology·Marcus J C LongYimon Aye
Jul 13, 2021·Frontiers in Cell and Developmental Biology·Hervé Técher, Philippe Pasero
Aug 17, 2021·DNA Repair·Samira KemihaPhilippe Pasero
Aug 28, 2021·Biomolecules·Commodore St GermainJacqueline H Barlow
Aug 30, 2021·Current Opinion in Genetics & Development·Yea-Lih Lin, Philippe Pasero
Sep 18, 2021·Proceedings of the National Academy of Sciences of the United States of America·Albert Serra-CardonaZhiguo Zhang

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