Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection

Nicolas, Estelle; Yamada, Tsuneo; Cam, Hugh P.; Fitzgerald, Peter; Kobayashi, Ryûji; Grewal, Shiv I. S.

doi:10.1038/nsmb1239

Cited by 175 publications

(266 citation statements)

References 60 publications

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“…This further supports the notion that HDAC inhibition stabilizes DSBs and/or increases DNA sensitivity to DSBs. In fission yeast, strains mutated for components of HDAC complexes are highly sensitive to genotoxic agents, with a massive accumulation of DSBs [53]. The same study also demonstrated that these strains increase antisense transcripts, suggesting that DSBs could be triggered by the presence of RNA-DNA hybrids, structures known to induce genomic instability [54].…”

Section: Sensitization To Exogenous Dna Damage By Hdacimentioning

confidence: 48%

Histone deacetylase inhibitors and genomic instability

Éot-Houllier¹,

Fulcrand²,

Magnaghi-Jaulin³

et al. 2009

Cancer Letters

113

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Abstract:Histone deacetylase inhibitors (HDACIs) are a promising new class of anticancer drugs.However, their mechanism of action has not been fully elucidated. Most studies have investigated the effect of HDACIs on the regulation of gene transcription. HDAC inhibition also leads to genomic instability by a variety of mechanisms. This phenomenon, which has been largely overlooked, may contribute to the cytotoxic effects of these drugs. Indeed, HDACIs sensitize DNA to exogenous genotoxic damage and induce the generation of reactive oxygen species. Moreover, HDACIs target mitosis resulting in chromosome segregation defects. Here, we review the effects of HDACI treatment on DNA damage and repair, and chromosome segregation control.

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Section: Sensitization To Exogenous Dna Damage By Hdacimentioning

confidence: 48%

Histone deacetylase inhibitors and genomic instability

Éot-Houllier¹,

Fulcrand²,

Magnaghi-Jaulin³

et al. 2009

Cancer Letters

113

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“…Furthermore, mRNAs are asymmetrically partitioned on centrosomes during mollusk embryonic cleavages (Lambert and Nagy, 2002). Finally, SpRrp6 and SpDis3 processes or degrade centromeric siRNAs that regulate kinetochore function (Murakami et al, 2007;Nicolas et al, 2007); whether these RNAs underlie the mechanism of metazoan Rrp6 action on mitotic chromosomes is unknown.…”

Section: Models For Rrp6 Function In Cell Cycle Progressionmentioning

confidence: 99%

“…The only core subunit linked to these phenomena is Csl4 (Baker et al, 1998) and that effect has been shown to be indirect (van Hoof et al, 2000). It has been suggested that the mitotic function of SpRrp6 and SpDis3 is to process or degrade centromere-associated small inhibitory RNAs (siRNAs; Buhler et al, 2007;Murakami et al, 2007;Nicolas et al, 2007). Whether these results in S. pombe explain the mitotic phenotypes associated with perturbation of Rrp6 and Dis3 in other eukaryotes is unknown.…”

mentioning

confidence: 99%

Core Exosome-independent Roles for Rrp6 in Cell Cycle Progression

Graham

Kiss²,

Andrulis

2009

MBoC

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Exosome complexes are 3 to 5 exoribonucleases composed of subunits that are critical for numerous distinct RNA metabolic (ribonucleometabolic) pathways. Several studies have implicated the exosome subunits Rrp6 and Dis3 in chromosome segregation and cell division but the functional relevance of these findings remains unclear. Here, we report that, in Drosophila melanogaster S2 tissue culture cells, dRrp6 is required for cell proliferation and error-free mitosis, but the core exosome subunit Rrp40 is not. Micorarray analysis of dRrp6-depleted cell reveals increased levels of cell cycleand mitosis-related transcripts. Depletion of dRrp6 elicits a decrease in the frequency of mitotic cells and in the mitotic marker phospho-histone H3 (pH3), with a concomitant increase in defects in chromosome congression, separation, and segregation. Endogenous dRrp6 dynamically redistributes during mitosis, accumulating predominantly but not exclusively on the condensed chromosomes. In contrast, core subunits localize predominantly to MTs throughout cell division. Finally, dRrp6-depleted cells treated with microtubule poisons exhibit normal kinetochore recruitment of the spindle assembly checkpoint protein BubR1 without restoring pH3 levels, suggesting that these cells undergo premature chromosome condensation. Collectively, these data support the idea that dRrp6 has a core exosome-independent role in cell cycle and mitotic progression. INTRODUCTIONExosome complexes are critical players in the processing and degradation of many RNA species (Houseley et al., 2006). Found in both archaebacteria and eukaryotes, these complexes are composed of a "core" set of subunits. With respect to the yeast and human core complexes, they consist of six RNase PH domain-containing proteins (Rrp41, Rrp42, Rrp43, Rrp45, Rrp46, and Mtr3) and three S1 domain-containing proteins (Rrp4, Rrp40, and Csl4). Our understanding of exosome complex form and function has advanced greatly though the report of the crystal structures of archaebacterial (Buttner et al., 2005; and eukaryotic exosome core (Liu et al., 2006) complexes. The RNase PH subunits assemble into a hexameric ring upon which the S1 domain subunits reside. It has been proposed that the cylindrical shape and central channel of exosome complexes have evolved as a means to tightly regulate RNA recognition and subsequent decay (Lorentzen and Conti, 2006).Eukaryotes have compartment-specific exosome subunits and cofactors in addition to the core subunits. Although the eubacterial RNase R homolog Dis3 (also referred to as Rrp44) interacts with the yeast core (Mitchell et al., 1997;Allmang et al., 1999b;Dziembowski et al., 2007), it does not associate with either the human or trypanosome core (Chen et al., 2001;Estevez et al., 2003). Moreover, many archaebacteria lack an RNase R-like protein (Koonin et al., 2001). Thus, strictly speaking, Dis3 is not a core exosome component. Another exosome subunit missing in archaebacteria but present in eukaryotes is Rrp6, an RNase D homolog. Rrp6 associates specifical...

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“…The HDACs Clr3 (a component of the SHREC (Snf2/Hdaccontaining repressor complex) silencing complex 23 ) and Clr6 (which exists in multi-subunit complexes 21 ) have been implicated in controlling Tf2 expression in S. pombe 10,21,23 . We investigated potential genetic interactions between HDACs and Abp1 in Tf2 silencing.…”

Section: Abp1 Recruits Hdacs To Tf2 and A Heterochromatic Locusmentioning

confidence: 99%

“…CENP-Bs bind to Tf2 retrotransposons and their remnants, and mediate Tf2 silencing by recruiting the class I histone deacetylase (HDAC) Clr6 (refs 21,22) and the class II HDAC Clr3 (ref. 23).…”

mentioning

confidence: 99%

Host genome surveillance for retrotransposons by transposon-derived proteins

Cam¹,

Noma²,

Ebina

et al. 2007

Nature

161

241

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Transposable elements and their remnants constitute a substantial fraction of eukaryotic genomes. Host genomes have evolved defence mechanisms, including chromatin modifications and RNA interference, to regulate transposable elements. Here we describe a genome surveillance mechanism for retrotransposons by transposase-derived centromeric protein CENP-B homologues of the fission yeast Schizosaccharomyces pombe. CENP-B homologues of S. pombe localize at and recruit histone deacetylases to silence Tf2 retrotransposons. CENP-Bs also repress solo long terminal repeats (LTRs) and LTR-associated genes. Tf2 elements are clustered into 'Tf' bodies, the organization of which depends on CENP-Bs that display discrete nuclear structures. Furthermore, CENP-Bs prevent an 'extinct' Tf1 retrotransposon from re-entering the host genome by blocking its recombination with extant Tf2, and silence and immobilize a Tf1 integrant that becomes sequestered into Tf bodies. Our results reveal a probable ancient retrotransposon surveillance pathway important for host genome integrity, and highlight potential conflicts between DNA transposons and retrotransposons, major transposable elements believed to have greatly moulded the evolution of genomes.

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Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection

Cited by 175 publications

References 60 publications

Histone deacetylase inhibitors and genomic instability

Histone deacetylase inhibitors and genomic instability

Core Exosome-independent Roles for Rrp6 in Cell Cycle Progression

Host genome surveillance for retrotransposons by transposon-derived proteins

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