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

Ghule, Prachi N.; Xie, Ronglin; Medina, Ricardo; Colby, Jennifer L.; Jones, Stephen N.; Lian, Jane B.; Stein, Janet L.; Wijnen, André J. van

doi:10.1128/mcb.01567-13

Cited by 26 publications

(45 citation statements)

References 60 publications

(65 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…80 Similarly, depletion of HiNF-P from cultured cells results in a dispersion of HLBs into smaller bodies, although they still form. 81,82 These data indicate that HiNF-P is not required for mammalian HLB formation but may promote complete HLB assembly via its role in H4 transcription.…”

Section: Self-organization Of the Hlbmentioning

confidence: 87%

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

2017

View full text Add to dashboard Cite

Metazoan replication-dependent (RD) histone genes encode the only known cellular mRNAs that are not polyadenylated. These mRNAs end instead in a conserved stem-loop, which is formed by an endonucleolytic cleavage of the pre-mRNA. The genes for all 5 histone proteins are clustered in all metazoans and coordinately regulated with high levels of expression during S phase. Production of histone mRNAs occurs in a nuclear body called the Histone Locus Body (HLB), a subdomain of the nucleus defined by a concentration of factors necessary for histone gene transcription and premRNA processing. These factors include the scaffolding protein NPAT, essential for histone gene transcription, and FLASH and U7 snRNP, both essential for histone pre-mRNA processing. Histone gene expression is activated by Cyclin E/Cdk2-mediated phosphorylation of NPAT at the G1-S transition. The concentration of factors within the HLB couples transcription with pre-mRNA processing, enhancing the efficiency of histone mRNA biosynthesis. KEYWORDSCell cycle; Drosophila; histone genes; mRNA processing; nuclear bodyProper utilization of genetic information in eukaryotes requires extensive three-dimensional organization of the genome and its associated proteins within the nucleus. The basic unit of genome organization is the nucleosome, an octamer of two molecules of each of the four core histone proteins (H2A, H2B, H3 and H4) that packages »147 base pairs of DNA. In mammalian cells, approximately 4£10 8 molcules of each core histone must be synthesized during S phase of the cell cycle to package the newly replicated DNA. Defects in this process result in genome instability that can contribute to human pathologies like cancer. Histone protein synthesis results from a large increase in production at the beginning of S phase of equal amounts of mRNAs encoding the four core nucleosomal histones, as well as histone H1. This highly coordinated gene expression event is performed by a set of transcription and pre-mRNA processing factors unique to replication dependent (RD) histone mRNA biosynthesis that assemble into a nuclear body tightly associated with RD histone genes called the histone locus body (HLB). HLB formation involves a combination of ordered and stochastic assembly steps, and cell cycle regulated changes in the HLB occur to activate histone gene expression during S phase. Here we describe the history of how the HLB was discovered followed by a discussion of HLB assembly mechanism and how the HLB functions in RD histone mRNA biosynthesis.

show abstract

Section: Self-organization Of the Hlbmentioning

confidence: 87%

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

2017

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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 ...

show abstract

“…[9][10][11][19][20][21] Our recent findings indicated that Hinfp-mediated control of histone H4 gene expression during S phase is essential for cell growth and proliferation. [22][23][24] Complete ablation of Hinfp in mice causes early embryonic lethality between embryonic day (E) 3.5 and E6.5. In vitro cultures of Hinfp-null embryos at E3.5 exhibit abnormal growth and proliferation.…”

Section: Introductionmentioning

confidence: 99%

“…22 Our studies also demonstrated that conditional removal of Hinfp in mouse embryonic fibroblasts (MEFs) resulted in reduced expression of histone H4 transcripts as well as protein and subsequently caused a spectrum of cell cycle and proliferation defects. 24 Inactivation of Hinfp and consequential reduction in histone H4 expression directly impacted nucleosomal assembly and generated replicative stress both during interphase and mitosis. 24 Thus, Hinfp may be a key regulatory factor that controls genomic stability.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

p53 checkpoint ablation exacerbates the phenotype of Hinfp dependent histone H4 deficiency

et al. 2015

Self Cite

View full text Add to dashboard Cite

Histone Nuclear Factor P (HINFP) is essential for expression of histone H4 genes. Ablation of Hinfp and consequential depletion of histones alter nucleosome spacing and cause stalled replication and DNA damage that ultimately result in genomic instability. Faithful replication and packaging of newly replicated DNA are required for normal cell cycle control and proliferation. The tumor suppressor protein p53, the guardian of the genome, controls multiple cell cycle checkpoints and its loss leads to cellular transformation. Here we addressed whether the absence of p53 impacts the outcomes/consequences of Hinfp-mediated histone H4 deficiency. We examined mouse embryonic fibroblasts lacking both Hinfp and p53. Our data revealed that the reduced histone H4 expression caused by depletion of Hinfp persists when p53 is also inactivated. Loss of p53 enhanced the abnormalities in nuclear shape and size (i.e. multi-lobed irregularly shaped nuclei) caused by Hinfp depletion and also altered the sub-nuclear organization of Histone Locus Bodies (HLBs). In addition to the polyploid phenotype resulting from deletion of either p53 or Hinfp, inactivation of both p53 and Hinfp increased mitotic defects and generated chromosomal fragility and susceptibility to DNA damage. Thus, our study conclusively establishes that simultaneous loss of both Hinfp and the p53 checkpoint is detrimental to normal cell growth and may predispose to cellular transformation.

show abstract

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

Cited by 26 publications

References 60 publications

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

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

p53 checkpoint ablation exacerbates the phenotype of Hinfp dependent histone H4 deficiency

Contact Info

Product

Resources

About