Sae2 and Rif2 regulate MRX endonuclease activity at DNA double-strand breaks in opposite manners

Marsella, Antonio; Gobbini, Elisa; Cassani, Corinne; Tisi, Renata; Cannavó, Elda; Reginato, Giordano; Ćejka, Petr; Longhese, Maria Pia

doi:10.1016/j.celrep.2021.108906

Cited by 19 publications

(32 citation statements)

References 76 publications

(172 reference statements)

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“…The MRX complex plays a central role in the repair of double-strand breaks (DSBs) (Oh & Symington, 2018), so why does Rif2 play such a negligible role? It has recently been reported that Rif2 and Sae2 have opposing roles in regulating the MRX complex, and the role of Rif2 in DSB repair is more readily detected in the absence of Sae2 (Marsella et al, 2021). While Sae2 has a prominent role in DSB repair, it has a minor role at telomeres; the inverse is true of Rif2 at DSBs and telomeres (Bonetti et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae

Bringas

Stinus

Zoeten

et al. 2022

eLife

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Rap1 is the main protein that binds double-stranded telomeric DNA in Saccharomyces cerevisiae. Examination of the telomere functions of Rap1 is complicated by the fact that it also acts as a transcriptional regulator of hundreds of genes and is encoded by an essential gene. In this study, we disrupt Rap1 telomere association by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant telomeric repeats. tlc1-tm cells grow similar to wild-type cells, although depletion of Rap1 at telomeres causes defects in telomere length regulation and telomere capping. Rif2 is a protein normally recruited to telomeres by Rap1, but we show that Rif2 can still associate with Rap1-depleted tlc1-tm telomeres, and that this association is required to inhibit telomere degradation by the MRX complex. Rif2 and the Ku complex work in parallel to prevent tlc1-tm telomere degradation; tlc1-tm cells lacking Rif2 and the Ku complex are inviable. The partially redundant mechanisms may explain the rapid evolution of telomere components in budding yeast species.

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Section: Discussionmentioning

confidence: 99%

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae

Bringas

Stinus

Zoeten

et al. 2022

eLife

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“…For Rad53 detection, protein extracts for western blot analysis were prepared by trichloroacetic acid (TCA) precipitation, as described previously ( 26 ). Proteins were resolved by SDS-PAGE (Bio-Rad 10% Mini-PROTEAN ® TGX™ Precast Protein Gels) and transferred onto PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

Eukaryotic stress–induced mutagenesis is limited by a local control of translesion synthesis

Masłowska¹,

Villafañez²,

Laureti³

et al. 2022

Nucleic Acids Research

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The DNA damage response (DDR) preserves the genetic integrity of the cell by sensing and repairing damages after a genotoxic stress. Translesion Synthesis (TLS), an error-prone DNA damage tolerance pathway, is controlled by PCNA ubiquitination. In this work, we raise the question whether TLS is controlled locally or globally. Using a recently developed method that allows to follow the bypass of a single lesion inserted into the yeast genome, we show that (i) TLS is controlled locally at each individual lesion by PCNA ubiquitination, (ii) a single lesion is enough to induce PCNA ubiquitination and (iii) PCNA ubiquitination is imperative for TLS to occur. More importantly, we show that the activation of the DDR that follows a genotoxic stress does not increase TLS at individual lesions. We conclude that unlike the SOS response in bacteria, the eukaryotic DDR does not promote TLS and mutagenesis.

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“…The MRX complex plays a central role in the repair of double-strand breaks (DSBs) (Oh & Symington, 2018), so why does Rif2 play such a negligible role? It has recently been reported that Rif2 and Sae2 have opposing roles in regulating the MRX complex, and the role of Rif2 in DSB repair is more readily detected in the absence of Sae2 (Marsella et al, 2021). While Sae2 has a prominent role in DSB repair, it has a minor role at telomeres (Bonetti et al, 2009); the inverse is true of Rif2 at DSBs and telomeres.…”

Section: Discussionmentioning

confidence: 99%

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae

Bringas

Stinus

Wanders

et al. 2020

Preprint

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SummaryRap1 is the main protein that binds double-stranded telomeric DNA in Saccharomyces cerevisiae. Rap1 can also bind and promote the formation of G-quadruplexes, which are thought to form at telomeres. Examination of the telomere functions of Rap1 is complicated by the fact that it also acts as a transcriptional regulator of hundreds of genes and is encoded by an essential gene. In this study, we disrupt Rap1 telomere association and G-quadruplex formation by expressing a mutant telomerase RNA subunit (tlc1-tm) that introduces mutant telomeric repeats. Remarkably, tlc1-tm cells grow as well as wild-type cells, although depletion of Rap1 at telomeres causes defects in telomere length regulation and telomere capping. We find that Rap1, Rif2, and the Ku complex work in parallel to prevent telomere degradation, and absence of all three causes lethality. The partially redundant mechanisms may explain the rapid evolution of telomere components in budding yeast species.

show abstract

Sae2 and Rif2 regulate MRX endonuclease activity at DNA double-strand breaks in opposite manners

Cited by 19 publications

References 76 publications

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae

Eukaryotic stress–induced mutagenesis is limited by a local control of translesion synthesis

Rif2 protects Rap1-depleted telomeres from MRX-mediated degradation in Saccharomyces cerevisiae

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