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Mrc1 and Rad9 cooperate to regulate initiation and elongation of DNA replication in response to DNA damage
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2018 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 37, no 21, article id e99319Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2018. Vol. 37, no 21, article id e99319
Keywords [en]
DNA replication, S‐phase checkpoint, elongation, initiation
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-151327DOI: 10.15252/embj.201899319ISI: 000449944900003PubMedID: 30158111OAI: oai:DiVA.org:umu-151327DiVA, id: diva2:1244366
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2019-01-08Bibliographically approved

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Sharma, SushmaChabes, Andrei

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Department of Medical Biochemistry and BiophysicsMolecular Infection Medicine Sweden (MIMS)
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CiteExportLink to record
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Citation style
  • apa
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  • de-DE
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Output format
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