Stress-Free with Rpd3: a Unique Chromatin Complex Mediates the Response to Oxidative Stress

McDaniel, Stephen L.; Strahl, Brian D.

doi:10.1128/mcb.01000-13

Cited by 10 publications

(11 citation statements)

References 16 publications

(13 reference statements)

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“…The Student's t-test was applied to assess significance. Sardiu et al 2009;McDaniel and Strahl 2013). Loss of RCO1 disrupts Rpd3S, whereas SDS3 or DEP1 deletions disrupt Rpd3L.…”

Section: Recombination Assaysmentioning

confidence: 99%

“…Rpd3S is directed by Eaf3 to methylated histone H3K36, predominantly found at the 39 end of coding regions, to repress cryptic transcription (Carrozza et al 2005b). Rpd3 was recently reported in a third complex, Rpd3m, along with the Snt2 and Ecm5 subunits ( Figure 1A) (Shevchenko et al 2008;McDaniel and Strahl 2013). This complex is enriched at promoter regions and has a role in the response to oxidative stress (Baker et al 2013), but little else is yet known about its function.…”

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confidence: 99%

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Bypassing the Requirement for an Essential MYST Acetyltransferase

Torres-Machorro

Pillus

2014

Genetics

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Histone acetylation is a key regulatory feature for chromatin that is established by opposing enzymatic activities of lysine acetyltransferases (KATs/HATs) and deacetylases (KDACs/HDACs). Esa1, like its human homolog Tip60, is an essential MYST family enzyme that acetylates histones H4 and H2A and other nonhistone substrates. Here we report that the essential requirement for ESA1 in Saccharomyces cerevisiae can be bypassed upon loss of Sds3, a noncatalytic subunit of the Rpd3L deacetylase complex. By studying the esa1Δ sds3Δ strain, we conclude that the essential function of Esa1 is in promoting the cellular balance of acetylation. We demonstrate this by fine-tuning acetylation through modulation of HDACs and the histone tails themselves. Functional interactions between Esa1 and HDACs of class I, class II, and the Sirtuin family define specific roles of these opposing activities in cellular viability, fitness, and response to stress. The fact that both increased and decreased expression of the ESA1 homolog TIP60 has cancer associations in humans underscores just how important the balance of its activity is likely to be for human well-being.T HE genetic information of DNA is packed into chromatin, which is predominantly composed of the H3, H4, H2A, and H2B core histone proteins that together with DNA form nucleosomes, the basic subunits of the genome (Kornberg and Lorch 1999). Chromatin structure regulates many cellular processes including gene expression, DNA replication, DNA damage repair, and recombination (Felsenfeld and Groudine 2003). Nucleosomes themselves are tightly regulated by mobilization and positioning that are mediated by ATP-dependent chromatin-remodeling machines (Rando and Winston 2012) and by multiple types of histone posttranslational modifications that include acetylation and many other marks (Campos and Reinberg 2009).Nucleosome acetylation is a highly dynamic modification that is promoted by HATs and removed by HDACs. HATs are classified by sequence into different families (Allis et al. 2007). ESA1/KAT5 belongs to the widely conserved MYST HAT family, named for its founding members (MOZ-YBF2/ SAS3-SAS2-TIP60) (Lafon et al. 2007). Esa1 is an essential HAT in yeast (Smith et al. 1998;Clarke et al. 1999) and the catalytic subunit of two distinct multi-protein complexes: NuA4 and Piccolo (Boudreault et al. 2003). Notably, the human homolog of Esa1 is Tip60, which is also essential in vertebrates and has been linked to multiple human diseases (Squatrito et al. 2006;Avvakumov and Côté 2007;Lafon et al. 2007), thus increasing the relevance of gaining a deeper understanding of essential HAT functions.Esa1 primarily acetylates H4 and H2A in vivo (Clarke et al. 1999;Lin et al. 2008) and regulates the expression of active protein-encoding genes (Reid et al. 2000;Lin et al. 2008). It plays a crucial role in cell cycle progression and ribosomal DNA (rDNA) silencing (Clarke et al. 1999(Clarke et al. , 2006 and is recruited to DNA double-strand breaks (DSBs) to promote damage repair by acetylati...

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“…The Student's t-test was applied to assess significance. Sardiu et al 2009;McDaniel and Strahl 2013). Loss of RCO1 disrupts Rpd3S, whereas SDS3 or DEP1 deletions disrupt Rpd3L.…”

Section: Recombination Assaysmentioning

confidence: 99%

mentioning

confidence: 99%

Bypassing the Requirement for an Essential MYST Acetyltransferase

Torres-Machorro

Pillus

2014

Genetics

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“…Cold Spring Harbor Laboratory Press on March 24, 2019 -Published by genome.cshlp.org Downloaded from (GO:1077; P = 0.005) (Supplemental Table S8), represented by PDR3, RIM101, RPN4, UME6, and CAT8, which are all direct or indirect regulators of stress response genes (Wendler et al 1997;Nishizawa et al 2010;Wang et al 2010;Soontorngun et al 2012;McDaniel and Strahl 2013). For instance, an enriched DSB-associated region ;15 kb downstream from ARS1013 (Fig.…”

Section: Mechanism Of Hydroxyurea-induced Chromosome Breaksmentioning

confidence: 99%

Break-seq reveals hydroxyurea-induced chromosome fragility as a result of unscheduled conflict between DNA replication and transcription

et al. 2015

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We have previously demonstrated that in Saccharomyces cerevisiae replication, checkpoint inactivation via a mec1 mutation leads to chromosome breakage at replication forks initiated from virtually all origins after transient exposure to hydroxyurea (HU), an inhibitor of ribonucleotide reductase. Here we sought to determine whether all replication forks containing single-stranded DNA gaps have equal probability of producing double-strand breaks (DSBs) when cells attempt to recover from HU exposure. We devised a new methodology, Break-seq, that combines our previously described DSB labeling with next generation sequencing to map chromosome breaks with improved sensitivity and resolution. We show that DSBs preferentially occur at genes transcriptionally induced by HU. Notably, different subsets of the HU-induced genes produced DSBs in MEC1 and mec1 cells as replication forks traversed a greater distance in MEC1 cells than in mec1 cells during recovery from HU. Specifically, while MEC1 cells exhibited chromosome breakage at stress-response transcription factors, mec1 cells predominantly suffered chromosome breakage at transporter genes, many of which are the substrates of those transcription factors. We propose that HU-induced chromosome fragility arises at higher frequency near HUinduced genes as a result of destabilized replication forks encountering transcription factor binding and/or the act of transcription. We further propose that replication inhibitors can induce unscheduled encounters between replication and transcription and give rise to distinct patterns of chromosome fragile sites.

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“…In Saccharomyces cerevisiae , Rpd3 constitutes the catalytic subunit of two well-known HDAC complexes, ScRpd3L and ScRpd3S, and of the newly characterized complex ScRpd3μ (31). In C. albicans , Rpd3 and Rpd31 are two putative orthologues of ScRpd3 sharing sequence identities of 75% and 84%, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…(A) Schematic cartoons of Rpd3L and Rpd3S complexes from S. cerevisiae (31). Green ovals indicate three core components shared by both complexes; gray and red ovals indicate the components specific to each complex, wherein ovals with white and bold letters indicate homologous components identified in C. albicans via immunoprecipitation in the present work.…”

Section: Resultsmentioning

confidence: 99%

The Paralogous Histone Deacetylases Rpd3 and Rpd31 Play Opposing Roles in Regulating the White-Opaque Switch in the Fungal Pathogen Candida albicans

Xie

Jenull

Tscherner

et al. 2016

mBio

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Chromatin modifications affect gene regulation in response to environmental stimuli in numerous biological processes. For example, N-acetyl-glucosamine and CO2 induce a morphogenetic conversion between white (W) and opaque (O) cells in MTL (mating-type locus) homozygous and heterozygous (a/α) strains of the human fungal pathogen Candida albicans. Here, we identify 8 histone-modifying enzymes playing distinct roles in the regulation of W/O switching in MTL homozygous and heterozygous strains. Most strikingly, genetic removal of the paralogous genes RPD3 and RPD31, both of which encode almost identical orthologues of the yeast histone deacetylase (HDAC) Rpd3, reveals opposing roles in W/O switching of MTLa/α strains. We show that Rpd3 and Rpd31 functions depend on MTL genotypes. Strikingly, we demonstrate that Rpd3 and Rpd31, which are almost identical except for a divergent C-terminal extension present in Rpd31, exert their functions in distinct regulatory complexes referred to as CaRpd3L and CaRpd31S complexes. Moreover, we identify the Candida orf19.7185 product Ume1, the orthologue of yeast Ume1, as a shared core subunit of CaRpd3L and CaRpd31S. Mechanistically, we show that the opposing roles of Rpd3 and Rpd31 require their deacetylase activities. Importantly, CaRpd3L interacts with the heterodimeric transcriptional repressor a1/α2, thus controlling expression of WOR1 encoding the master regulator of W/O switching. Thus, our work provides novel insight about regulation mechanisms of W/O switching in MTLa/α strains. This is the first example of two highly conserved HDACs exerting opposing regulatory functions in the same process in a eukaryotic cell.

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Stress-Free with Rpd3: a Unique Chromatin Complex Mediates the Response to Oxidative Stress

Cited by 10 publications

References 16 publications

Bypassing the Requirement for an Essential MYST Acetyltransferase

Bypassing the Requirement for an Essential MYST Acetyltransferase

Break-seq reveals hydroxyurea-induced chromosome fragility as a result of unscheduled conflict between DNA replication and transcription

The Paralogous Histone Deacetylases Rpd3 and Rpd31 Play Opposing Roles in Regulating the White-Opaque Switch in the Fungal Pathogen Candida albicans

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