11/21/2023 0 Comments Okazaki fragment scholarly fragmentEK is a National Science Foundation (NSF) Graduate Research Fellow. The intramural Research Programs of the National Human Genome Research Institute supported KM. The work is made available under the Creative Commons CC0 public domain dedication.įunding: This work was supported by National Institutes of Health (NIH) grant GM074917 to AKB, who is a Scholar of the Leukemia and Lymphoma Society. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Received: NovemAccepted: Published: June 18, 2013 PLoS ONE 8(6):Įditor: Marco Muzi-Falconi, Universita’ di Milano, Italy (2013) Unligated Okazaki Fragments Induce PCNA Ubiquitination and a Requirement for Rad59-Dependent Replication Fork Progression. Thus, we propose that Rad59 promotes fork progression when Okazaki fragment processing is compromised and counteracts PCNA-K107 mediated cell cycle arrest.Ĭitation: Nguyen HD, Becker J, Thu YM, Costanzo M, Koch EN, Smith S, et al. Since Mrc1 resides at the replication fork and is phosphorylated in response to fork stalling, these results indicate that Rad59 alleviates nick-induced replication fork slowdown. In comparison to cdc9 single mutants, cdc9 rad59Δ double mutants did not alter PCNA ubiquitination but enhanced phosphorylation of the mediator of the replication checkpoint, Mrc1. To further understand how cells cope with the accumulation of nicks during DNA replication, we utilized cdc9-1 in a genome-wide synthetic lethality screen, which identified RAD59 as a strong negative interactor. Both enzymes reversed PCNA ubiquitination, arguing that the modification is likely an integral part of a novel nick-sensory mechanism and not due to non-specific secondary mutations that could have occurred spontaneously in cdc9 mutants. To determine whether PCNA ubiquitination occurred in response to nicks or was triggered by the lack of PCNA-DNA ligase interaction, we complemented cdc9 cells with either wild-type DNA ligase I or a mutant form, which fails to interact with PCNA. We report here that a pol30-K107 mutation alleviated cell cycle delay in cdc9 mutants, consistent with the idea that the modification of PCNA at K107 affects the rate of DNA synthesis at replication forks. This signal is crucial to activate the S phase checkpoint, which promotes cell cycle delay. Deficiency in DNA ligase I, encoded by CDC9 in budding yeast, leads to the accumulation of unligated Okazaki fragments and triggers PCNA ubiquitination at a non-canonical lysine residue.
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