Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress

Simoneau, Antoine; Ricard, Étienne; Weber, Sandra; Hammond-Martel, Ian; Wong, Lai Hong; Sellam, Adnane; Giaever, Guri; Nislow, Corey; Raymond, Martine; Würtele, Hugo

doi:10.1093/nar/gkv1537

Cited by 23 publications

(55 citation statements)

References 107 publications

(160 reference statements)

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“…While the precise consequences of Rad53 “hyperactivation” are incompletely characterized, its biological relevance is highlighted by the fact that it causes sensitivity to replicative stress-inducing drugs [ 31 ]. Interestingly, we and others have shown that limiting Rad53 activation via DOT1 deletion or histone gene mutations that inhibit H3K79me promotes resistance to DNA replication-blocking drugs in several yeast mutants, including hst3Δ hst4Δ cells, by elevating usage of error-prone translesion synthesis (TLS) [ 22 , 33 – 35 ]. These observations emphasize the importance of the interplay between chromatin and DNA damage checkpoint signalling in regulating the cellular response to replicative stress.…”

Section: Introductionmentioning

confidence: 99%

“…A genetic screen conducted by our group in S . cerevisiae identified yku70Δ and yku80Δ mutants as sensitive to pharmacological inhibition of sirtuin HDACs by nicotinamide (NAM) [ 35 ]. Since NAM causes replicative stress [ 35 ], we originally postulated that the Yku70/80 complex might influence DNA replication progression in the absence of sirtuin activity.…”

Section: Introductionmentioning

confidence: 99%

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An interplay between multiple sirtuins promotes completion of DNA replication in cells with short telomeres

2018

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The evolutionarily-conserved sirtuin family of histone deacetylases regulates a multitude of DNA-associated processes. A recent genome-wide screen conducted in the yeast Saccharomyces cerevisiae identified Yku70/80, which regulate nonhomologous end-joining (NHEJ) and telomere structure, as being essential for cell proliferation in the presence of the pan-sirtuin inhibitor nicotinamide (NAM). Here, we show that sirtuin-dependent deacetylation of both histone H3 lysine 56 and H4 lysine 16 promotes growth of yku70Δ and yku80Δ cells, and that the NAM sensitivity of these mutants is not caused by defects in DNA double-strand break repair by NHEJ, but rather by their inability to maintain normal telomere length. Indeed, our results indicate that in the absence of sirtuin activity, cells with abnormally short telomeres, e.g., yku70/80Δ or est1/2Δ mutants, present striking defects in S phase progression. Our data further suggest that early firing of replication origins at short telomeres compromises the cellular response to NAM- and genotoxin-induced replicative stress. Finally, we show that reducing H4K16ac in yku70Δ cells limits activation of the DNA damage checkpoint kinase Rad53 in response to replicative stress, which promotes usage of translesion synthesis and S phase progression. Our results reveal a novel interplay between sirtuin-mediated regulation of chromatin structure and telomere-regulating factors in promoting timely completion of S phase upon replicative stress.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An interplay between multiple sirtuins promotes completion of DNA replication in cells with short telomeres

2018

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“…Our study cautions that conclusions derived from such experiments may require additional scrutiny. In particular, two recent studies have examined sensitivity of yeast deletion mutants to nicotinamide on a genome-wide scale, identifying a plethora of strains that are both sensitive and resistant to concentrations of 20 mM or higher Simoneau et al 2016). While these results were discussed in the context of sirtuin biology, our novel study suggests that sirtuin-independent effects should also be considered.…”

Section: Novel Targets For Nicotinamide?mentioning

confidence: 92%

Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases

et al. 2016

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Nicotinamide is both a reaction product and an inhibitor of the conserved sirtuin family of deacetylases, which have been implicated in a broad range of cellular functions in eukaryotes from yeast to humans. Phenotypes observed following treatment with nicotinamide are most often assumed to stem from inhibition of one or more of these enzymes. Here, we used this small molecule to inhibit multiple sirtuins at once during treatment with DNA damaging agents in the Saccharomyces cerevisiae model system. Since sirtuins have been previously implicated in the DNA damage response, we were surprised to observe that nicotinamide actually increased the survival of yeast cells exposed to the DNA damage agent MMS. Remarkably, we found that enhanced resistance to MMS in the presence of nicotinamide was independent of all five yeast sirtuins. Enhanced resistance was also independent of the nicotinamide salvage pathway, which uses nicotinamide as a substrate to generate NAD+, and of a DNA damage-induced increase in the salvage enzyme Pnc1. Our data suggest a novel and unexpected function for nicotinamide that has broad implications for its use in the study of sirtuin biology across model systems.KEYWORDS nicotinamide; sirtuins; DNA damage; checkpoint; Pnc1; NAD+ T HE DNA damage checkpoint is a highly conserved signaling cascade initiated in response to DNA lesions. In the budding yeast Saccharomyces cerevisiae, checkpoint activation begins with the exposure of single-stranded DNA (ssDNA), either from exonuclease-resected DNA doublestrand breaks (DSBs), or from stalled replication forks during S phase. Resected DNA coated by the ssDNA binding protein RPA is thought to act as a landing pad for Mec1-Ddc2 complexes (Melo and Toczyski 2002;Gobbini et al. 2013;Edenberg et al. 2014a). Mec1 is a sensor kinase that, in concert with adaptor proteins such as Rad9 or Mrc1, phosphorylates downstream checkpoint targets, including the Rad53 and Chk1 transducing kinases (Melo and Toczyski 2002;Gobbini et al. 2013; Bastos de Oliveira et al. 2015). Following autophosphorylation and release from adaptors, Rad53 is thought to move throughout the cell to phosphorylate targets that promote cell cycle arrest, the inhibition of late-firing origins of replication, and a global transcriptional response (Melo and Toczyski 2002;Jaehnig et al. 2013;Edenberg et al. 2014a). While the DNA damage response is traditionally associated with phosphorylationbased signaling cascades, it has recently emerged that other post-translational modifications including ubiquitylation, sumoylation, and acetylation play prominent roles in the response in both yeast and other eukaryotes (Downey and Durocher 2006a;Psakhye and Jentsch 2012;Panier and Durocher 2013;Edenberg et al. 2014a;Elia et al. 2015).Acetylation of lysine residues is catalyzed by histone acetyltransferases (HATs) and reversed by histone deacetylases (HDACs). Despite their names, these enzymes also have nonhistone targets that play critical roles in maintaining cellular homeostasis in organisms from ba...

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“…These histone modifications are related to the different states of chromatin and regulate distinct histone-involved processes, including DNA replication, gene transcription and DNA repair [3, 5, 7, 13]. Histone modifications also affect chromatin assembly in various ways, including the regulation of histone folding and processing, histone nuclear import, and the interaction between histones and histone chaperones [25, 27–29].…”

Section: Introductionmentioning

confidence: 99%

“…Dysregulation of histone H3K56 acetylation leads to increased sensitivity to DNA damage agents and elevated genome instability [37, 44, 45]. Both hyper- and hypo-acetylation of H3K56 result in defects in sister chromatid cohesion, recombination and ribosomal DNA (rDNA) amplification [27, 33]. H3K56Ac makes the nucleosome termini more flexible and facilitates nucleosome disassembly [41, 46, 47].…”

Section: Introductionmentioning

confidence: 99%

Potential Functions of Histone H3.3K56 Acetylation in Mammals

Fang

Chen

Zhang

et al. 2020

Preprint

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H3K56 acetylation (H3K56Ac) was first identified in yeast and has recently been reported to play important roles in maintaining genomic stability, chromatin assembly, DNA replication, cell cycle progression and DNA repair. Although H3.1K56Ac has been relatively well studied, the function of H3.3K56Ac remains mostly unknown in mammals. In this study, we used H3.3K56Q and H3.3K56R mutants to study the possible function of H3.3K56 acetylation. The K-to-Q substitution mimics a constitutively acetylated lysine, while the K-to-R replacement mimics a constitutively unmodified lysine. We report that cell lines harboring mutation of H3.3K56R exhibit dramatic morphology changes and cell death. Using Tet-Off inducible system, we show an increased population of polyploid/aneuploid cells and a decreased cell viability in H3.3K56R mutant cells. In consistence with these results, H3.3K56R mutant compromised H3.3 incorporation into several pericentric and centric heterochromatin regions we tested. Moreover, mass spectrometry analysis coupled with label free quantification reveal that biological processes regulated by the H3.3-associating proteins, whose interaction with H3.3 is markedly increased by H3.3K56Q mutation but decreased by H3.3K56Q mutation, include sister chromatid cohesion, mitotic nuclear division, and mitotic nuclear envelope disassembly. These results suggest that H3.3K56 acetylation is crucial for chromosome segregation and cell division in mammals. ∼ 30% of total histone H3. However, in mammalian cells its abundance is much lower as it marks less than 1% of total H3 [34]. H3K56Ac is tightly regulated by cell cycle and DNA damage-induced checkpoints [30, 32]. In budding yeast, H3K56 has been reported to be acetylated predominantly during the S phase, but deacetylated rapidly when cells enter the G2/M phase of the cell cycle [32, 43]. Mammalian H3K56 acetylation requires the histone chaperone Asf1 and occurs mainly at the S phase in unstressed cells [37, 42]. Dysregulation of histone H3K56 acetylation leads to increased sensitivity to DNA damage agents and elevated genome instability [37, 44, 45]. Both hyper-and hypo-acetylation of H3K56 result in defects in sister chromatid cohesion ， recombination and ribosomal DNA (rDNA) amplification [27, 33].H3K56Ac makes the nucleosome termini more flexible and facilitates nucleosome disassembly [41, 46, 47]. H3K56Ac also alters the substrate specificity of SWR-C, leading to either H2A.Z or H2A being exchanged from nucleosomes [48]. These findings strongly support the important role of H3K56 acetylation in regulating cell cycle progression, DNA damage response, chromatin remodeling, nucleosome assembly following DNA replication and DNA repair.However, all these reports focused on K56Ac of H3, either on H3.1 or without defining which isoform of H3. Studies on K56Ac of the variant H3.3 in mammals in particular are absent and remain to be explored.In this study, to address the function of H3.3K56 acetylation, we made use of H3.3K56Q and H3.3K56R mutants, in which the lysine at...

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Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of DNA damage-induced signaling upon replicative stress

Cited by 23 publications

References 107 publications

An interplay between multiple sirtuins promotes completion of DNA replication in cells with short telomeres

An interplay between multiple sirtuins promotes completion of DNA replication in cells with short telomeres

Nicotinamide Suppresses the DNA Damage Sensitivity of Saccharomyces cerevisiae Independently of Sirtuin Deacetylases

Potential Functions of Histone H3.3K56 Acetylation in Mammals

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