How yeast cells deal with stalled replication forks

Arbel, Matan; Liefshitz, Batia; Kupiec, Martin

doi:10.1007/s00294-020-01082-y

Cited by 16 publications

(9 citation statements)

References 45 publications

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“…The stalled replication fork can be rescued by different pathways, including a direct bypass of the lesion or template switching where the newly synthesised DNA strand serves as a template (Unk et al 2010). Post-translational modifications of PCNA, a homotrimer ring-like protein, regulates the re-start/repair of the stalled fork (Moldovan et al 2007;Arbel et al 2020;Ripley et al 2020). Ubiquitylation of PCNA by the Rad6/Rad18 complex activates the DNA damage tolerance pathway (Hoege et al 2002) whereas PCNA SUMOylation inhibits unwanted recombination events at the stalled fork (Papouli et al 2005;Pfander et al 2005;Motegi et al 2006;Burkovics et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Mgs1 function at G-quadruplex structures during DNA replication

Paeschke

Burkovics

2020

Curr Genet

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The coordinated action of DNA polymerases and DNA helicases is essential at genomic sites that are hard to replicate. Among these are sites that harbour G-quadruplex DNA structures (G4). G4s are stable alternative DNA structures, which have been implicated to be involved in important cellular processes like the regulation of gene expression or telomere maintenance. G4 structures were shown to hinder replication fork progression and cause genomic deletions, mutations and recombination events. Many helicases unwind G4 structures and preserve genome stability, but a detailed understanding of G4 replication and the re-start of stalled replication forks around formed G4 structures is not clear, yet. In our recent study, we identified that Mgs1 preferentially binds to G4 DNA structures in vitro and is associated with putative G4-forming chromosomal regions in vivo. Mgs1 binding to G4 motifs in vivo is partially dependent on the helicase Pif1. Pif1 is the major G4-unwinding helicase in S. cerevisiae. In the absence of Mgs1, we determined elevated gross chromosomal rearrangement (GCR) rates in yeast, similar to Pif1 deletion. Here, we highlight the recent findings and set these into context with a new mechanistic model. We propose that Mgs1's functions support DNA replication at G4-forming regions.

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Section: Introductionmentioning

confidence: 99%

Mgs1 function at G-quadruplex structures during DNA replication

Paeschke

Burkovics

2020

Curr Genet

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“…This is consistent with these S-phase specific lesions inducing different repair pathways, including post-replication repair via translesion synthesis and template switching to repair MMS-induced damage, as well as nucleolytic cleavage of protein - DNA adducts to repair CPT-induced damages (rev. in (Alagoz et al 2012; Arbel, Liefshitz, and Kupiec 2020)).…”

Section: Resultsmentioning

confidence: 99%

Schizosaccharomyces pombeKAT5 contributes to resection and repair of a DNA double strand break

Petreaca

Forsburg

2020

Preprint

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10Chromatin remodeling is essential for effective repair of a DNA double strand break. KAT5 (S. pombe Mst1, 11 human TIP60) is a MYST family histone acetyltransferase conserved from yeast to humans that coordinates 12 various DNA damage response activities at a DSB, including histone remodeling and activation of the DNA 13 damage checkpoint. In S. pombe, mutations in mst1+ causes sensitivity to DNA damaging drugs. Here we show 14 that Mst1 is recruited to DSBs. Mutation of mst1+ disrupts recruitment of repair proteins and delays resection. 15These defects are partially rescued by deletion of pku70, which has been previously shown to antagonize repair 16 by homologous recombination. These phenotypes of mst1 are similar to pht1-4KR, a non-acetylatable form of 17 histone variant H2A.Z, which has been proposed to affect resection. These data suggest that Mst1 functions to 18 direct repair of DSBs towards homologous recombination pathways by modulating resection at the double strand 19 break. 20 21 the most highly conserved HAT of this family, known as Mst1 in S. pombe, Esa1 in S. cerevisiae, and TIP60 in 34 mammals (reviewed in (Avvakumov and Côté 2007; Pillus 2008)). The gene is essential for viability in all species, 35 because in addition to its role in DSB repair it performs other functions such as transcriptional regulation, 36 heterochromatin assembly and centromere assembly (Doyon and Côté 2004; Ghobashi and Kamel 2018; Gómez 37 et al. 2008; Nugent et al. 2010; Pillus 2008). In humans, TIP60 has also been identified as a tumor suppressor 38 (rev. (Sapountzi, Logan, and Robson 2006; Voss and Thomas 2009) and is a therapeutic target (rev. in (Judes et 39 al. 2015). 40 KAT5 contains a chromodomain in addition to its HAT domain, which suggests that it binds methylated 41 histones (rev. in (De La Cruz et al. 2005; Utley and Côté 2003)). KAT5 functions in the context of a large protein 42 complex called NuA4, and acetylates numerous substrates including histones H2A, H3, and H4, and the histone 43

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“…In contrast to DSBs, where HR processes are facilitated, there are redundant mechanisms to prevent recombination at stalled forks; these mechanisms include disassembly of Rad51 filaments, helicases that abort recombination intermediates, and nucleases that degrade aberrant structures. PCNA is SUMOylated (SUMO-PCNA), facilitating the binding of the helicase Srs2, which suppresses recombination by disassembling Rad51 filaments (for review, see [109]. Recombination intermediates are aborted by the BLM ortholog Sgs1 helicase; indeed, the sgs1 srs2 double mutants is not viable but viability is rescued when HR is defective [110].…”

Section: Intra-s Phase Checkpoint and Stabilization Of The Replication Forkmentioning

confidence: 99%

Checkpoint Control of DNA Repair in Yeast

Fasullo¹

2021

Saccharomyces

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Budding yeast has been a model organism for understanding how DNA damage is repaired and how cells minimize genetic instability caused by arresting or delaying the cell cycle at well-defined checkpoints. However, many DNA damage insults are tolerated by mechanisms that can both be error-prone and error-free. The mechanisms that tolerate DNA damage and promote cell division are less well-understood. This review summarizes current information known about the checkpoint response to agents that elicit both the G2/M checkpoint and the intra-S phase checkpoint and how cells adapt to unrepaired DNA damage. Tolerance to particular bulky DNA adducts and radiomimetic agents are discussed, as well as possible mechanisms that may control phosphatases that deactivate phosphorylated proteins.

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How yeast cells deal with stalled replication forks

Cited by 16 publications

References 45 publications

Mgs1 function at G-quadruplex structures during DNA replication

Mgs1 function at G-quadruplex structures during DNA replication

Schizosaccharomyces pombeKAT5 contributes to resection and repair of a DNA double strand break

Checkpoint Control of DNA Repair in Yeast

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