The Rad5 Helicase and RING Domains Contribute to Genome Stability through their Independent Catalytic Activities

Toth, Robert; Balogh, D.; Pintér, Lajos; Jaksa, Gábor; Szeplaki, Bence; Gráf, Alexandra; Györfy, Zsuzsanna; Enyedi, Marton Zs.; Kiss, Ernö; Haracska, Lajos; Unk, Ildikó

doi:10.1016/j.jmb.2021.167437

Cited by 5 publications

(3 citation statements)

References 58 publications

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“…Only if bypass and restart mechanisms fail, and additionally the fork is not resolved by an oncoming replication fork from another origin, must further potentially mutagenic options be explored. Once disconnected from the CMG helicase, a stalled fork gains the capability to reverse by re‐annealing the nascent leading and lagging strands to yield a 4‐pronged structure akin to a Holliday Junction and capable of migration over significant distances, a remodelling process assisted by Rad5 in budding yeast (Figure 3b) (Blastyak et al, 2007; Toth et al, 2022; Unk et al, 2010). Reversed replication forks gain a free double‐stranded end, which can be resected and initiate homologous recombination (Cotta‐Ramusino et al, 2005; Lemacon et al, 2017).…”

Section: Mechanisms For Ensuring Replisome Processivitymentioning

confidence: 99%

Transcription as source of genetic heterogeneity in budding yeast

Piguet,

Houseley

2024

Yeast

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Transcription presents challenges to genome stability both directly, by altering genome topology and exposing single‐stranded DNA to chemical insults and nucleases, and indirectly by introducing obstacles to the DNA replication machinery. Such obstacles include the RNA polymerase holoenzyme itself, DNA‐bound regulatory factors, G‐quadruplexes and RNA‐DNA hybrid structures known as R‐loops. Here, we review the detrimental impacts of transcription on genome stability in budding yeast, as well as the mitigating effects of transcription‐coupled nucleotide excision repair and of systems that maintain DNA replication fork processivity and integrity. Interactions between DNA replication and transcription have particular potential to induce mutation and structural variation, but we conclude that such interactions must have only minor effects on DNA replication by the replisome with little if any direct mutagenic outcome. However, transcription can significantly impair the fidelity of replication fork rescue mechanisms, particularly Break Induced Replication, which is used to restart collapsed replication forks when other means fail. This leads to de novo mutations, structural variation and extrachromosomal circular DNA formation that contribute to genetic heterogeneity, but only under particular conditions and in particular genetic contexts, ensuring that the bulk of the genome remains extremely stable despite the seemingly frequent interactions between transcription and DNA replication.

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Section: Mechanisms For Ensuring Replisome Processivitymentioning

confidence: 99%

Transcription as source of genetic heterogeneity in budding yeast

Piguet,

Houseley

2024

Yeast

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“…Remarkably, both ATPase and helicase domains overlap with the E3 ligase activity (see Section 3.2.3 ) through the polyubiquitination of PCNA, making it difficult to determine whether the helicase domain plays a catalytic role during DNA damage bypass. Through in vivo and in vitro characterization of helicase domain-specific mutants, Toth et al show that the Walker B motif of the helicase domain is not necessary for Rad5-Ubc13 interaction, and that the Rad5 RING and helicase domains can function independently of each other [ 216 ].…”

Section: Post-translational Modifications Of Pcna and The Ddt Pathwaysmentioning

confidence: 99%

Post-Translational Modifications of PCNA: Guiding for the Best DNA Damage Tolerance Choice

Bellı́

Colomina

Castells‐Roca

et al. 2022

JoF

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The sliding clamp PCNA is a multifunctional homotrimer mainly linked to DNA replication. During this process, cells must ensure an accurate and complete genome replication when constantly challenged by the presence of DNA lesions. Post-translational modifications of PCNA play a crucial role in channeling DNA damage tolerance (DDT) and repair mechanisms to bypass unrepaired lesions and promote optimal fork replication restart. PCNA ubiquitination processes trigger the following two main DDT sub-pathways: Rad6/Rad18-dependent PCNA monoubiquitination and Ubc13-Mms2/Rad5-mediated PCNA polyubiquitination, promoting error-prone translation synthesis (TLS) or error-free template switch (TS) pathways, respectively. However, the fork protection mechanism leading to TS during fork reversal is still poorly understood. In contrast, PCNA sumoylation impedes the homologous recombination (HR)-mediated salvage recombination (SR) repair pathway. Focusing on Saccharomyces cerevisiae budding yeast, we summarized PCNA related-DDT and repair mechanisms that coordinately sustain genome stability and cell survival. In addition, we compared PCNA sequences from various fungal pathogens, considering recent advances in structural features. Importantly, the identification of PCNA epitopes may lead to potential fungal targets for antifungal drug development.

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“…A rad5-IA ubikvitin ligáz [111,117] és az mms2 [140,141] Modellünkben a Rad5 három független funkcióval rendelkezik (39. ábra) [144]. Az egyik ezek közül a villavisszafordítás, melyben a Rad5 helikáz/ATPáz aktivitása vesz részt.…”

Section: éRtékelésunclassified

A Saccharomyces cerevisiae Rad5 aktivitásainak genetikai vizsgálata

Toth

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The Rad5 Helicase and RING Domains Contribute to Genome Stability through their Independent Catalytic Activities

Cited by 5 publications

References 58 publications

Transcription as source of genetic heterogeneity in budding yeast

Transcription as source of genetic heterogeneity in budding yeast

Post-Translational Modifications of PCNA: Guiding for the Best DNA Damage Tolerance Choice

A Saccharomyces cerevisiae Rad5 aktivitásainak genetikai vizsgálata

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