Are multiple checkpoint mediators involved in a checkpoint linking histone gene expression with DNA replication?

Histone proteins are essential for the packaging of DNA into chromosomes. Histone gene expression is cell-cycle-regulated and coupled to DNA replication. Control of histone gene expression occurs at the transcriptional and post-transcriptional level and ensures that a fine balance between histone abundance and DNA replication is maintained for the correct packaging of newly replicated DNA into chromosomes. In the present paper, we review histone gene expression, highlighting the control mechanisms and key molecules involved in this process.

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Distinct replication-independent and -dependent phases of histone gene expression during the Physarum cell cycle.

Molecular and Cellular Biology ◽

10.1128/mcb.7.5.1933 ◽

1987 ◽

Vol 7 (5) ◽

pp. 1933-1937 ◽

Cited By ~ 5

Author(s):

J J Carrino ◽

V Kueng ◽

R Braun ◽

T G Laffler

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Dna Replication ◽

Dna Synthesis ◽

S Phase ◽

Histone Gene ◽

Histone Mrna ◽

Histone Gene Expression ◽

Tightly Coupled ◽

G2 Phase

During the S phase of the cell cycle, histone gene expression and DNA replication are tightly coupled. In mitotically synchronous plasmodia of the myxomycete Physarum polycephalum, which has no G1 phase, histone mRNA synthesis begins in mid-G2 phase. Although histone gene transcription is activated in the absence of significant DNA synthesis, our data demonstrate that histone gene expression became tightly coupled to DNA replication once the S phase began. There was a transition from the replication-independent phase to the replication-dependent phase of histone gene expression. During the first phase, histone mRNA synthesis appears to be under direct cell cycle control; it was not coupled to DNA replication. This allowed a pool of histone mRNA to accumulate in late G2 phase, in anticipation of future demand. The second phase began at the end of mitosis, when the S phase began, and expression became homeostatically coupled to DNA replication. This homeostatic control required continuing protein synthesis, since cycloheximide uncoupled transcription from DNA synthesis. Nuclear run-on assays suggest that in P. polycephalum this coupling occurs at the level of transcription. While histone gene transcription appears to be directly switched on in mid-G2 phase and off at the end of the S phase by cell cycle regulators, only during the S phase was the level of transcription balanced with the rate of DNA synthesis.

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Replication stress-induced alternative mRNA splicing alters properties of the histone RNA-binding protein HBP/SLBP: a key factor in the control of histone gene expression

Bioscience Reports ◽

10.1042/bsr20130074 ◽

2013 ◽

Vol 33 (5) ◽

Cited By ~ 1

Author(s):

Alexander M. J. Rattray ◽

Pamela Nicholson ◽

Berndt Müller

Keyword(s):

Gene Expression ◽

Alternative Splicing ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Replication Stress ◽

S Phase ◽

Histone Gene ◽

Histone Genes ◽

Histone Gene Expression

Animal replication-dependent histone genes produce histone proteins for the packaging of newly replicated genomic DNA. The expression of these histone genes occurs during S phase and is linked to DNA replication via S-phase checkpoints. The histone RNA-binding protein HBP/SLBP (hairpin-binding protein/stem-loop binding protein), an essential regulator of histone gene expression, binds to the conserved hairpin structure located in the 3′UTR (untranslated region) of histone mRNA and participates in histone pre-mRNA processing, translation and histone mRNA degradation. Here, we report the accumulation of alternatively spliced HBP/SLBP transcripts lacking exons 2 and/or 3 in HeLa cells exposed to replication stress. We also detected a shorter HBP/SLBP protein isoform under these conditions that can be accounted for by alternative splicing of HBP/SLBP mRNA. HBP/SLBP mRNA alternative splicing returned to low levels again upon removal of replication stress and was abrogated by caffeine, suggesting the involvement of checkpoint kinases. Analysis of HBP/SLBP cellular localization using GFP (green fluorescent protein) fusion proteins revealed that HBP/SLBP protein and isoforms lacking the domains encoded by exon 2 and exons 2 and 3 were found in the nucleus and cytoplasm, whereas HBP/SLBP lacking the domain encoded by exon 3 was predominantly localised to the nucleus. This isoform lacks the conserved region important for protein–protein interaction with the CTIF [CBP80/20 (cap-binding protein 80/20)]-dependent initiation translation factor and the eIF4E (eukaryotic initiation factor 4E)-dependent translation factor SLIP1/MIF4GD (SLBP-interacting protein 1/MIF4G domain). Consistent with this, we have previously demonstrated that this region is required for the function of HBP/SLBP in cap-dependent translation. In conclusion, alternative splicing allows the synthesis of HBP/SLBP isoforms with different properties that may be important for regulating HBP/SLBP functions during replication stress.

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Distinct replication-independent and -dependent phases of histone gene expression during the Physarum cell cycle

Molecular and Cellular Biology ◽

10.1128/mcb.7.5.1933-1937.1987 ◽

1987 ◽

Vol 7 (5) ◽

pp. 1933-1937

Author(s):

J J Carrino ◽

V Kueng ◽

R Braun ◽

T G Laffler

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Dna Replication ◽

Dna Synthesis ◽

S Phase ◽

Histone Gene ◽

Histone Mrna ◽

Histone Gene Expression ◽

Tightly Coupled ◽

G2 Phase

During the S phase of the cell cycle, histone gene expression and DNA replication are tightly coupled. In mitotically synchronous plasmodia of the myxomycete Physarum polycephalum, which has no G1 phase, histone mRNA synthesis begins in mid-G2 phase. Although histone gene transcription is activated in the absence of significant DNA synthesis, our data demonstrate that histone gene expression became tightly coupled to DNA replication once the S phase began. There was a transition from the replication-independent phase to the replication-dependent phase of histone gene expression. During the first phase, histone mRNA synthesis appears to be under direct cell cycle control; it was not coupled to DNA replication. This allowed a pool of histone mRNA to accumulate in late G2 phase, in anticipation of future demand. The second phase began at the end of mitosis, when the S phase began, and expression became homeostatically coupled to DNA replication. This homeostatic control required continuing protein synthesis, since cycloheximide uncoupled transcription from DNA synthesis. Nuclear run-on assays suggest that in P. polycephalum this coupling occurs at the level of transcription. While histone gene transcription appears to be directly switched on in mid-G2 phase and off at the end of the S phase by cell cycle regulators, only during the S phase was the level of transcription balanced with the rate of DNA synthesis.

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Transcriptional and Post-Transcriptional Control of Histone Gene Expression

Chromosomal Proteins and Gene Expression ◽

10.1007/978-1-4684-7615-6_11 ◽

1985 ◽

pp. 171-176

Author(s):

Daniel Schümperli

Keyword(s):

Gene Expression ◽

Transcriptional Control ◽

Histone Gene ◽

Histone Gene Expression

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Super resolution light microscopy of the Drosophila Histone Locus Body reveals a core-shell organization associated with expression of replication dependent histone genes

Molecular Biology of the Cell ◽

10.1091/mbc.e20-10-0645 ◽

2021 ◽

pp. mbc.E20-10-0645

Author(s):

James P. Kemp ◽

Xiao-Cui Yang ◽

Zbigniew Dominski ◽

William F. Marzluff ◽

Robert J. Duronio

Keyword(s):

Gene Expression ◽

Gene Transcription ◽

Nuclear Body ◽

Histone Gene ◽

Core Shell ◽

Histone Genes ◽

The Core ◽

Histone Gene Expression ◽

Histone Locus ◽

Histone Gene Transcription

The Histone Locus Body (HLB) is an evolutionarily conserved nuclear body that regulates the transcription and processing of replication-dependent (RD) histone mRNAs, which are the only eukaryotic mRNAs lacking a poly-A tail. Many nuclear bodies contain distinct domains, but how internal organization is related to nuclear body function is not fully understood. Here, we demonstrate using structured illumination microscopy that Drosophila HLBs have a “core-shell” organization in which the internal core contains transcriptionally active RD histone genes. The N-terminus of Mxc, which contains a domain required for Mxc oligomerization, HLB assembly, and RD histone gene expression, is enriched in the HLB core. In contrast, the C-terminus of Mxc is enriched in the HLB outer shell as is FLASH, a component of the active U7 snRNP that co-transcriptionally cleaves RD histone pre-mRNA. Consistent with these results, we show biochemically that FLASH binds directly to the Mxc C-terminal region. In the rapid S-M nuclear cycles of syncytial blastoderm Drosophila embryos, the HLB disassembles at mitosis and reassembles the core-shell arrangement as histone gene transcription is activated immediately after mitosis. Thus, the core-shell organization is coupled to zygotic histone gene transcription, revealing a link between HLB internal organization and RD histone gene expression.

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Effect of adenovirus infection on expression of human histone genes.

Molecular and Cellular Biology ◽

10.1128/mcb.4.7.1363 ◽

1984 ◽

Vol 4 (7) ◽

pp. 1363-1371 ◽

Cited By ~ 20

Author(s):

S J Flint ◽

M A Plumb ◽

U C Yang ◽

G S Stein ◽

J L Stein

Keyword(s):

Gene Expression ◽

Dna Synthesis ◽

Histone Gene ◽

Adenovirus Infection ◽

Histone Genes ◽

Histone Mrna ◽

Intact Cells ◽

Mrna Species ◽

Histone Gene Expression ◽

Infected Cells

The influence of adenovirus type 2 infection of HeLa cells upon expression of human histone genes was examined as a function of the period of infection. Histone RNA synthesis was assayed after run-off transcription in nuclei isolated from mock-infected cells and after various periods of adenovirus infection. Histone protein synthesis was measured by [3H]leucine labeling of intact cells and fluorography of electrophoretically fractionated nuclear and cytoplasmic proteins. The cellular representation of RNA species complementary to more than 13 different human histone genes was determined by RNA blot analysis of total cellular, nuclear or cytoplasmic RNA by using a series of 32P-labeled cloned human histone genes as hybridization probes and also by analysis of 3H-labeled histone mRNA species synthesized in intact cells. By 18 h after infection, HeLa cell DNA synthesis and all parameters of histone gene expression, including transcription and the nuclear and cytoplasmic concentrations of core and H1 mRNA species, were reduced to less than 5 to 10% of the control values. By contrast, transcription and processing of other cellular mRNA sequences have been shown to continue throughout this period of infection. The early period of adenovirus infection was marked by an inhibition of transcription of histone genes that accompanied the reduction in rate of HeLa cell DNA synthesis. These results suggest that the adenovirus-induced inhibition of histone gene expression is mediated in part at the transcriptional level. However, the persistence of histone mRNA species at concentrations comparable to those of mock-infected control cells during the early phase of the infection, despite a reduction in histone gene transcription and histone protein synthesis, implies that histone gene expression is also regulated post-transcriptionally in adenovirus-infected cells. These results suggest that the tight coupling between histone mRNA concentrations and the rate of cellular DNA synthesis, observed when DNA replication is inhibited by a variety of drugs, is not maintained after adenovirus infection.

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