The DNA damage checkpoint: A tale from budding yeast

Pizzul, Paolo; Casari, Erika; Gnugnoli, Marco; Rinaldi, Carlo; Corallo, Flavio; Longhese, Maria Pia

doi:10.3389/fgene.2022.995163

Cited by 27 publications

(20 citation statements)

References 152 publications

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“…In mitotic cells, it is well‐established that the introduction of DSBs induces local and global association of Scc1/Rad21‐cohesin to the yeast and mammalian chromosomes. In the budding yeast, DSBs induce DDR, which activates two sensor kinases, Mec1(ATR) and Tel1(ATM), and the downstream kinases, Rad53 and Chk1/2 for the efficient DSB repair and cell cycle delay/arrest (Pizzul et al, 2022). Importantly, with DSB induction, the miotic cohesin complex is loaded at the DSB sites locally and to chromosomes globally (Strom et al, 2007; Unal et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

DNA double‐strand breaks regulate the cleavage‐independent release of Rec8‐cohesin during yeast meiosis

Fajish,

Challa,

Salim

et al. 2023

Genes to Cells

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The mitotic cohesin complex necessary for sister chromatid cohesion and chromatin loop formation shows local and global association to chromosomes in response to DNA double‐strand breaks (DSBs). Here, by genome‐wide binding analysis of the meiotic cohesin with Rec8, we found that the Rec8‐localization profile along chromosomes is altered from middle to late meiotic prophase I with cleavage‐independent dissociation. Each Rec8‐binding site on the chromosome axis follows a unique alternation pattern with dissociation and probably association. Centromeres showed altered Rec8 binding in late prophase I relative to mid‐prophase I, implying chromosome remodeling of the regions. Rec8 dissociation ratio per chromosome is correlated well with meiotic DSB density. Indeed, the spo11 mutant deficient in meiotic DSB formation did not change the distribution of Rec8 along chromosomes in late meiotic prophase I. These suggest the presence of a meiosis‐specific regulatory pathway for the global binding of Rec8‐cohesin in response to DSBs.

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Section: Discussionmentioning

confidence: 99%

DNA double‐strand breaks regulate the cleavage‐independent release of Rec8‐cohesin during yeast meiosis

Fajish,

Challa,

Salim

et al. 2023

Genes to Cells

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“…Mec1/ATR, recruited to RPA–ssDNA filaments due to replication fork catastrophe, associates with its partner Ddc2 (ATRIP in humans). This coordination results in histone H2A phosphorylation and a subsequent pause in the cell cycle through Rad53 (CHK1 in humans) phosphorylation reviewed in refs and . Proteomic studies have determined that Mec1/ATR phosphorylates other replisome proteins during ongoing DNA synthesis, and may play other functions at the fork that are distinct from their canonical checkpoint role during replication stress .…”

Section: Obstaclesmentioning

confidence: 99%

Embracing Heterogeneity: Challenging the Paradigm of Replisomes as Deterministic Machines

Lewis,

van Oijen,

Spenkelink

2023

Chem. Rev.

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The paradigm of cellular systems as deterministic machines has long guided our understanding of biology. Advancements in technology and methodology, however, have revealed a world of stochasticity, challenging the notion of determinism. Here, we explore the stochastic behavior of multi-protein complexes, using the DNA replication system (replisome) as a prime example. The faithful and timely copying of DNA depends on the simultaneous action of a large set of enzymes and scaffolding factors. This fundamental cellular process is underpinned by dynamic protein–nucleic acid assemblies that must transition between distinct conformations and compositional states. Traditionally viewed as a well-orchestrated molecular machine, recent experimental evidence has unveiled significant variability and heterogeneity in the replication process. In this review, we discuss recent advances in single-molecule approaches and single-particle cryo-EM, which have provided insights into the dynamic processes of DNA replication. We comment on the new challenges faced by structural biologists and biophysicists as they attempt to describe the dynamic cascade of events leading to replisome assembly, activation, and progression. The fundamental principles uncovered and yet to be discovered through the study of DNA replication will inform on similar operating principles for other multi-protein complexes.

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“…HR occurs after resection, the 5′→3′ nucleolytic digestion of DSB ends that exposes single-stranded DNA (ssDNA) and leads to formation of a Rad51-ssDNA filament, and can generate reciprocal crossovers (RCOs) [3]. Alongside specific repair processes, DNA damage prompts a broader DDR that involves checkpoint signaling, which arrests the cell cycle while DNA damage is repaired [5]. Here, histone H2A-S129 phosphorylation (γH2A) is placed by the Mec1 and Tel1 sensor kinases around lesions, and forms a platform for the recruitment of other DDR factors, including checkpoint proteins [6].…”

Section: Introductionmentioning

confidence: 99%

Rtt107 cooperates with Rad55 or Slx4 to maintain genome stability inSaccharomyces cerevisiae

Brown,

Kobor

2024

Preprint

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A range of genome maintenance factors respond to endogenous and exogenous DNA damage to prevent mutations and cell death. The scaffold protein, Rtt107, is important for the growth of cells exposed to DNA-damaging agents in the budding yeastSaccharomyces cerevisiae. Rtt107 binds to a diverse array of partner proteins, such as Slx4, and responds to DNA damage by localizing to phosphorylated histone H2A. Rad55–Rad57, a heterodimer involved in DNA repair, also binds to Rtt107, but the function of the Rtt107–Rad55–Rad57 complex remains unclear. In addition to their sensitivity to DNA-damaging agents,rtt107Δmutants exhibit spontaneous genome instability phenotypes, including spontaneous loss of heterozygosity (LOH) caused by crossovers and other genetic events. However, the binding partners with which Rtt107 interacts to prevent spontaneous genome instability have yet to be elucidated. Here, we showed that Rtt107 acts in the same pathway as Rad55 to limit LOH, specifically by preventing crossover events. Arad55-S404Aphosphorylation site mutation largely disrupted the interaction between Rtt107 and Rad55–Rad57, resulting in increased LOH and crossover rates, consistent with the contribution of Rtt107–Rad55–Rad57 interaction to genome stability. Strikingly, anrtt107-K887Mmutation that reduces Rtt107 recruitment to H2A did not result in an LOH phenotype, suggesting that the role of Rtt107 in preventing LOH is distinct from its function as an H2A-binding scaffold. Rtt107 did not function primarily in the same pathway as Rad55 to limit recombination at the sensitive ribosomal DNA (rDNA) locus, but instead acted with Slx4 to maintain rDNA stability, suggesting that interactions of Rtt107 with different partners prevented distinct types of instability. Taken together, our observations suggested that Rtt107 limits spontaneous LOH and crossover events in part by binding to Rad55 in a manner dependent on Rad55-S404.

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The DNA damage checkpoint: A tale from budding yeast

Cited by 27 publications

References 152 publications

DNA double‐strand breaks regulate the cleavage‐independent release of Rec8‐cohesin during yeast meiosis

DNA double‐strand breaks regulate the cleavage‐independent release of Rec8‐cohesin during yeast meiosis

Embracing Heterogeneity: Challenging the Paradigm of Replisomes as Deterministic Machines

Rtt107 cooperates with Rad55 or Slx4 to maintain genome stability inSaccharomyces cerevisiae

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