The Elg1 Replication Factor C-like Complex Functions in PCNA Unloading during DNA Replication

Kubota, Takashi; Nishimura, Kohei; Kanemaki, Masato T.; Donaldson, Anne

doi:10.1016/j.molcel.2013.02.012

Cited by 258 publications

(311 citation statements)

References 35 publications

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“…20,32 Delg1 mutants are sensitive to various DNA damaging agents, among them MMS. Surprisingly, the S112A mutation, which abolishes the MMS-induced phosphorylation, had no effect on the sensitivity to MMS (Fig.…”

Section: Elg1 Phosphorylation Is Not Required For Mms Resistancementioning

confidence: 99%

“…[13][14][15] The Elg1 RLC was shown to interact with PCNA, particularly when it is SUMOylated, and plays a role in unloading it from chromatin. 20,21 Human ELG1/ATAD5 has been shown to play an important role in maintaining genome stability in S phase. hELG1 knockdown leads to increased levels of recombination and chromosomal aberrations such as chromosomal fusions and inversions.…”

Section: Introductionmentioning

confidence: 99%

“…21 Genetic and biochemical experiments have shown that Elg1 interacts with PCNA, and particularly with SUMOylated PCNA. 20,21 Current models of Elg1 RLC activity 25 propose that it may be in charge of PCNA unloading during S-phase, or during repair. Elg1 may be important for unloading PCNA upon DNA Polymerase stalling at sites difficult to replicate or upon encounter with DNA lesions.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Elg1 activity by phosphorylation

et al. 2015

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These authors contributed equally to this work.Keywords: ATM/Tel1, ATR/Mec1, DNA damage response, DNA repair, DNA replication, telomeres ELG1 is a conserved gene with important roles in the maintenance of genome stability. Elg1's activity prevents gross chromosomal rearrangements, maintains proper telomere length regulation, helps repairing DNA damage created by a number of genotoxins and participates in sister chromatid cohesion. Elg1 is evolutionarily conserved, and its Fanconi Anemia-related mammalian ortholog (also known as ATAD5) is embryonic lethal when lost in mice and acts as a tumor suppressor in mice and humans. Elg1 encodes a protein that forms an RFC-like complex that unloads the replicative clamp, PCNA, from DNA, mainly in its SUMOylated form. We have identified 2 different regions in yeast Elg1 that undergo phosphorylation. Phosphorylation of one of them, S112, is dependent on the ATR yeast ortholog, Mec1, and probably is a direct target of this kinase. We show that phosphorylation of Elg1 is important for its role at telomeres. Mutants unable to undergo phosphorylation suppress the DNA damage sensitivity of Drad5 mutants, defective for an error-free post-replicational bypass pathway. This indicates a role of phosphorylation in the regulation of DNA repair. Our results open the way to investigate the mechanisms by which the activity of Elg1 is regulated during DNA replication and in response to DNA damage.

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Section: Elg1 Phosphorylation Is Not Required For Mms Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulation of Elg1 activity by phosphorylation

et al. 2015

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“…Budding yeast Elg1 and its homolog, ATAD5, in mammalian cells form an alternate replication factor C-like complex (Bellaoui et al 2003;Ben-Aroya et al 2003;Kanellis et al 2003) that promotes unloading of PCNA during replication (Kubota et al 2013;Lee et al 2013). This function is important for genome maintenance but is not essential for replication.…”

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confidence: 99%

Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication

et al. 2015

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Accurate completion of replication relies on the ability of cells to activate error-free recombination-mediated DNA damage bypass at sites of perturbed replication. However, as anti-recombinase activities are also recruited to replication forks, how recombination-mediated damage bypass is enabled at replication stress sites remained puzzling. Here we uncovered that the conserved SUMO-like domain-containing Saccharomyces cerevisiae protein Esc2 facilitates recombination-mediated DNA damage tolerance by allowing optimal recruitment of the Rad51 recombinase specifically at sites of perturbed replication. Mechanistically, Esc2 binds stalled replication forks and counteracts the anti-recombinase Srs2 helicase via a two-faceted mechanism involving chromatin recruitment and turnover of Srs2. Importantly, point mutations in the SUMO-like domains of Esc2 that reduce its interaction with Srs2 cause suboptimal levels of Rad51 recruitment at damaged replication forks. In conclusion, our results reveal how recombination-mediated DNA damage tolerance is locally enabled at sites of replication stress and globally prevented at undamaged replicating chromosomes.

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“…We have shown previously, by genetic tests, that ISW2 and NHP10 do not function through several genes involved in replication fork protection and DNA repair pathways (Vincent et al 2008), leading to the conclusion that they do not function via these pathways (Au et al 2011). However, these tests were not very quantitative, and additional genes involved in DNA damage response and replication fork protection were identified after our previous tests (Crabbe et al 2010;Engels et al 2011;Hegnauer et al 2012;Gonzalez-Prieto et al 2013;Kubota et al 2013). We therefore performed more comprehensive genetic tests to determine whether ISW2 and NHP10 function in these pathways.…”

Section: Isw2 and Ino80 Function Outside Of Dna Repair Or Fork Protecmentioning

confidence: 93%

Chromatin Remodeling Factors Isw2 and Ino80 Regulate Checkpoint Activity and Chromatin Structure in S Phase

2015

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When cells undergo replication stress, proper checkpoint activation and deactivation are critical for genomic stability and cell survival and therefore must be highly regulated. Although mechanisms of checkpoint activation are well studied, mechanisms of checkpoint deactivation are far less understood. Previously, we reported that chromatin remodeling factors Isw2 and Ino80 attenuate the S-phase checkpoint activity in Saccharomyces cerevisiae, especially during recovery from hydroxyurea. In this study, we found that Isw2 and Ino80 have a more pronounced role in attenuating checkpoint activity during late S phase in the presence of methyl methanesulfonate (MMS). We therefore screened for checkpoint factors required for Isw2 and Ino80 checkpoint attenuation in the presence of MMS. Here we demonstrate that Isw2 and Ino80 antagonize checkpoint activators and attenuate checkpoint activity in S phase in MMS either through a currently unknown pathway or through RPA. Unexpectedly, we found that Isw2 and Ino80 increase chromatin accessibility around replicating regions in the presence of MMS through a novel mechanism. Furthermore, through growth assays, we provide additional evidence that Isw2 and Ino80 partially counteract checkpoint activators specifically in the presence of MMS. Based on these results, we propose that Isw2 and Ino80 attenuate S-phase checkpoint activity through a novel mechanism.

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The Elg1 Replication Factor C-like Complex Functions in PCNA Unloading during DNA Replication

Cited by 258 publications

References 35 publications

Regulation of Elg1 activity by phosphorylation

Regulation of Elg1 activity by phosphorylation

Local regulation of the Srs2 helicase by the SUMO-like domain protein Esc2 promotes recombination at sites of stalled replication

Chromatin Remodeling Factors Isw2 and Ino80 Regulate Checkpoint Activity and Chromatin Structure in S Phase

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