Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway

Liang, Dun; Burkhart, Sarah Lyn; Singh, Rakesh Kumar; Kabbaj, Marie-Helene; Gunjan, Akash

doi:10.1093/nar/gks722

Cited by 49 publications

(61 citation statements)

References 106 publications

(165 reference statements)

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“…Such Hinfp deficiency-related replicative stress is likely to induce genomic instability and DNA damage during S phase. Several studies in yeast have shown that removal or altered dosage of other core nucleosomal proteins H3 and H2B in addition to H4 creates numerous cell growth defects, increased sensitivity to DNA damage, and altered nucleosome positioning (48)(49)(50)(51)(52)(53)(54)(55). Recent findings also show that perturbations in normal nucleosome spacing compromise transcription and genome integrity, as well as predispose dividing cells to tumorigenesis (56).…”

Section: Discussionmentioning

confidence: 99%

Fidelity of Histone Gene Regulation Is Obligatory for Genome Replication and Stability

Ghule

Xie

Medina

et al. 2014

Molecular and Cellular Biology

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bFidelity of chromatin organization is crucial for normal cell cycle progression, and perturbations in packaging of DNA may predispose to transformation. Histone H4 protein is the most highly conserved chromatin protein, required for nucleosome assembly, with multiple histone H4 gene copies encoding identical protein. There is a long-standing recognition of the linkage of histone gene expression and DNA replication. A fundamental and unresolved question is the mechanism that couples histone biosynthesis with DNA replication and fidelity of cell cycle control. Here, we conditionally ablated the obligatory histone H4 transcription factor HINFP to cause depletion of histone H4 in mammalian cells. Deregulation of histone H4 results in catastrophic cellular and molecular defects that lead to genomic instability. Histone H4 depletion increases nucleosome spacing, impedes DNA synthesis, alters chromosome complement, and creates replicative stress. Our study provides functional evidence that the tight coupling between DNA replication and histone synthesis is reciprocal.

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Section: Discussionmentioning

confidence: 99%

Fidelity of Histone Gene Regulation Is Obligatory for Genome Replication and Stability

Ghule

Xie

Medina

et al. 2014

Molecular and Cellular Biology

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“…The histone H3-R129E mutation weakens Asf1-H3 interaction without affecting the interaction between Asf1 and Rad53 (Agez et al 2007;Jiao et al 2012). In budding yeast, transcription of HHT2 contributes ∼85% of total H3 mRNA (Cross and Smith 1988;Liang et al 2012). We therefore introduced the HHT2-R129E mutation into our two-DSB system in the wild-type, asf1Δ, rtt101Δ, and rtt109Δ backgrounds.…”

Section: Degradation Of Rad53 Rescues the Recovery Defect Of Asf1δmentioning

confidence: 99%

Asf1 facilitates dephosphorylation of Rad53 after DNA double-strand break repair

et al. 2016

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To allow for sufficient time to repair DNA double-stranded breaks (DSBs), eukaryotic cells activate the DNA damage checkpoint. In budding yeast, Rad53 (mammalian Chk2) phosphorylation parallels the persistence of the unrepaired DSB and is extinguished when repair is complete in a process termed recovery or when the cells adapt to the DNA damage checkpoint. A strain containing a slowly repaired DSB does not require the histone chaperone Asf1 to resume cell cycle progression after DSB repair. When a second, rapidly repairable DSB is added to this strain, Asf1 becomes required for recovery. Recovery from two repairable DSBs also depends on the histone acetyltransferase Rtt109 and the cullin subunit Rtt101, both of which modify histone H3 that is associated with Asf1. We show that dissociation of histone H3 from Asf1 is required for efficient recovery and that Asf1 is required for complete dephosphorylation of Rad53 when the upstream DNA damage checkpoint signaling is turned off. Our data suggest that the requirements for recovery from the DNA damage checkpoint become more stringent with increased levels of damage and that Asf1 plays a histone chaperone-independent role in facilitating complete Rad53 dephosphorylation following repair.

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“…Consistent with a central role in histone gene expression is the synthetic lethality observed upon loss of the individual SAGA subunits Spt8, Spt20, and Gcn5 with deletion of the histone transcriptional activator Spt10 (Chang and Winston 2013). Normal cell cycle progression and DNA repair require precise regulation of histone levels (Singh et al 2009;Singh et al 2010;Eriksson et al 2012;Liang et al 2012;Ghule et al 2014), therefore restoration of histone expression likely contributes to the restored cell cycle progression and growth upon DNA damage that we observe in gcn5D cells overexpressing RTS1.At the end of S phase, Wee1 phosphorylates H2B-Y40 at histone gene promoters to downregulate expression (Mahajan et al 2012), but a counteracting phosphatase is unknown. Future work should determine whether PP2A Rts1 directly dephosphorylates H2BY40ph as part of the mechanism of histone gene activation.…”

mentioning

confidence: 92%

Promotion of Cell Viability and Histone Gene Expression by the Acetyltransferase Gcn5 and the Protein Phosphatase PP2A in Saccharomyces cerevisiae

et al. 2016

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Histone modifications direct chromatin-templated events in the genome and regulate access to DNA sequence information. There are multiple types of modifications, and a common feature is their dynamic nature. An essential step for understanding their regulation, therefore, lies in characterizing the enzymes responsible for adding and removing histone modifications. Starting with a dosagesuppressor screen in Saccharomyces cerevisiae, we have discovered a functional interaction between the acetyltransferase Gcn5 and the protein phosphatase 2A (PP2A) complex, two factors that regulate post-translational modifications. We find that RTS1, one of two genes encoding PP2A regulatory subunits, is a robust and specific high-copy suppressor of temperature sensitivity of gcn5D and a subset of other gcn5D phenotypes. Conversely, loss of both PP2A Rts1 and Gcn5 function in the SAGA and SLIK/SALSA complexes is lethal. RTS1 does not restore global transcriptional defects in gcn5D; however, histone gene expression is restored, suggesting that the mechanism of RTS1 rescue includes restoration of specific cell cycle transcripts. Pointing to new mechanisms of acetylation-phosphorylation cross-talk, RTS1 high-copy rescue of gcn5D growth requires two residues of H2B that are phosphorylated in human cells. These data highlight the potential significance of dynamic phosphorylation and dephosphorylation of these deeply conserved histone residues for cell viability. KEYWORDS chromatin; transcription; phosphorylation; acetylation (IOC2, PAB1, RHO2, MED6, ZDS1, PP2A B56 ) A T the foundation of nuclear DNA organization in eukaryotes is the dynamic formation, movement, and modification of nucleosomes. Acetylation and phosphorylation are two histone post-translational modifications (PTMs) catalyzed by histone acetyltransferases (HATs) and kinases and reversed by histone deacetylases (HDACs) and phosphatases that alter nucleosome structure and function. Tightly regulated acetylation and phosphorylation of specific histone residues have deeply conserved functions in eukaryotes that are critical for transcriptional regulation, replication, repair, and segregation of eukaryotic genomes (Banerjee and Chakravarti 2011;Rossetto et al. 2012;Tessarz and Kouzarides 2014).One well-conserved HAT is Gcn5, which specifically targets histones H3 and H2B as part of multiple complexes (Grant et al. 1997;Eberharter et al. 1999;Grant et al. 1999;Howe et al. 2001;Sterner et al. 2002;Pray-Grant et al. 2005). Gcn5 is a key regulator of eukaryotic gene expression and acetylates H3 at promoters of active genes (Pokholok et al. 2005;Nagy and Tora 2007;Rosaleny et al. 2007). Its role as a transcriptional activator is so fundamental that Gcn5 is essential in most eukaryotes studied. An exception of note is budding yeast, where deletion of GCN5 is tolerated, but does cause a spectrum of phenotypes, including defects in gene activation, particularly for stress-regulated genes, and altered cell cycle progression (Howe et al. 2001;Huisinga and Pugh 2004;Vernarecci ...

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Histone dosage regulates DNA damage sensitivity in a checkpoint-independent manner by the homologous recombination pathway

Cited by 49 publications

References 106 publications

Fidelity of Histone Gene Regulation Is Obligatory for Genome Replication and Stability

Fidelity of Histone Gene Regulation Is Obligatory for Genome Replication and Stability

Asf1 facilitates dephosphorylation of Rad53 after DNA double-strand break repair

Promotion of Cell Viability and Histone Gene Expression by the Acetyltransferase Gcn5 and the Protein Phosphatase PP2A in Saccharomyces cerevisiae

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