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

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

doi:10.1080/15384101.2015.1049783

Cited by 15 publications

(15 citation statements)

References 41 publications

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“…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: 92%

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

2017

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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.

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Section: Self-organization Of the Hlbmentioning

confidence: 92%

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

2017

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“…Deregulation of histone gene expression upon loss of HINFP or NPAT causes disruption of HLBs and has drastic consequences for cell division and cell survival in both normal and cancer cells (Di Fruscio et al, ; Ghule et al, , ; Ma et al, ). The resulting changes in the organization of newly replicated chromatin create both genomic instability and chromosomal aberrations, that are frequently observed during tumorigenesis.…”

Section: Histone Gene Expression In Nuclear Microenvironmentsmentioning

confidence: 99%

“…Recently it was demonstrated that Hinfp‐mediated deregulation of histone H4 results in cellular and molecular defects that lead to genomic instability. Functional evidence has been provided that the tight coupling between DNA replication and histone synthesis is reciprocal (Ghule et al, ) Furthermore, simultaneous loss of Hinfp and p53 exacerbates cellular defects (Ghule et al, ). We observed that siRNA‐depletion of HINFP‐regulated H4 mRNAs causes genomic instability (unpublished data).…”

Section: Hinfp Is An Essential Regulator Of Histone Gene Transcriptiomentioning

confidence: 99%

Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S‐phase transition

Ghule

Seward²,

Fritz

et al. 2018

Journal Cellular Physiology

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Fidelity of histone gene regulation, and ultimately of histone protein biosynthesis, is obligatory for packaging of newly replicated DNA into chromatin. Control of histone gene expression within the 3-dimensional context of nuclear organization is reflected by two well documented observations. DNA replication-dependent histone mRNAs are synthesized at specialized subnuclear domains designated histone locus bodies (HLBs), in response to activation of the growth factor dependent Cyclin E/CDK2/HINFP/NPAT pathway at the G1/S transition in mammalian cells. Complete loss of the histone gene regulatory factors HINFP or NPAT disrupts HLB integrity that is necessary for coordinate control of DNA replication and histone gene transcription. Here we review the molecular histone-related requirements for G1/S-phase progression during the cell cycle. Recently developed experimental strategies, now enable us to explore mechanisms involved in dynamic control of histone gene expression in the context of the temporal (cell cycle) and spatial (HLBs) remodeling of the histone gene loci.

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“…Loss of Hinfp causes replicative stress and DNA damage (Ghule et al, 2014) and simultaneous loss of the tumor suppressor protein p53 exacerbates proliferative defects in cell culture models (Ghule et al, 2015). Therefore, we investigated whether loss of Hinfp provokes DNA damage in E3.5 stage embryos using accumulation of phospho-H2AX (Ser-139) foci as a marker for double-stranded DNA breaks.…”

Section: Resultsmentioning

confidence: 99%

“…The immediate cellular consequences of H4 deficiency are structural changes in chromatin organization that predispose to DNA damage and aneuploidy (Ghule et al, 2015; Ghule et al, 2014). These genomic changes ultimately generate cell cycle arrest and/or cell death.…”

Section: Discussionmentioning

confidence: 99%

Maternal expression and early induction of histone gene transcription factor Hinfp sustains development in pre-implantation embryos

Ghule

Xie

Colby

et al. 2016

Developmental Biology

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Fidelity of histone gene expression is important for normal cell growth and differentiation that is stringently controlled during development but is compromised during tumorigenesis. Efficient production of histones for packaging newly replicated DNA is particularly important for proper cell division and epigenetic control during the initial pre-implantation stages of embryonic development. Here, we addressed the unresolved question of when the machinery for histone gene transcription is activated in the developing zygote to accommodate temporal demands for histone gene expression. We examined induction of Histone Nuclear Factor P (HINFP), the only known transcription factor required for histone H4 gene expression, that binds directly to a unique H4 promoter-specific element to regulate histone H4 transcription. We show that Hinfp gene transcripts are stored in oocytes and maternally transmitted to the zygote. Transcripts from the paternal Hinfp gene, which reflect induction of zygotic gene expression, are apparent at the 4- to 8-cell stage, when most maternal mRNA pools are depleted. Loss of Hinfp expression due to gene ablation reduces cell numbers in E3.5 stage embryos and compromises implantation. Reduced cell proliferation is attributable to severe reduction in histone mRNA levels accompanied by reduced cell survival and genomic damage as measured by cleaved Caspase 3 and phospho-H2AX staining, respectively. We conclude that transmission of maternal Hinfp transcripts and zygotic activation of the Hinfp gene together are necessary to control H4 gene expression in early pre-implantation embryos in order to support normal embryonic development.

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

Cited by 15 publications

References 41 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

Higher order genomic organization and regulatory compartmentalization for cell cycle control at the G1/S‐phase transition

Maternal expression and early induction of histone gene transcription factor Hinfp sustains development in pre-implantation embryos

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