Knockdown of SLBP results in nuclear retention of histone mRNA

Sullivan, Kelly D.; Mullen, Thomas E.; Marzluff, William F.; Wagner, Eric J.

doi:10.1261/rna.1205409

Cited by 91 publications

(122 citation statements)

References 58 publications

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“…34,82 A disruption of SLBP, a central regulator of histone mRNA metabolism, is deleterious for embryonic development of several organisms, resulting in chromosome condensation defect in Drosophila and C. elegans 83,84 and DNA replication failure in mouse oocytes. 85 Human somatic cells with depleted SLBP are viable, although their growth rate is significantly impaired due to a delayed progression through S phase as a result of inefficient DNA synthesis, [52][53][54] thus producing a similar phenotype as ABCE1 silencing in our study. It is hence tempting to speculate that the involvement in histone synthesis may be one of the vital functions of ABCE1.…”

Section: Discussionsupporting

confidence: 63%

“…51 As shown previously, inhibition of histone synthesis via the depletion of the stem-loop binding protein (SLBP) resulted in a decreased rate of DNA synthesis mediated by the S phase checkpoint activation, which also slowed down S phase progression. [52][53][54] To investigate a possible link between DNA synthesis and histone expression in our study, we analyzed the steady-state levels of two core histone proteins, H2B and H4, which indeed appeared to be clearly reduced (to 55-60% of the control value) in ABCE1-depleted HEK293 cells (Fig. 3B).…”

Section: Abce1 Downregulation Impairs Cell Proliferation and Cell Cycmentioning

confidence: 97%

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ABCE1 is essential for S phase progression in human cells

et al. 2016

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ABCE1 is a highly conserved protein universally present in eukaryotes and archaea, which is crucial for the viability of different organisms. First identified as RNase L inhibitor, ABCE1 is currently recognized as an essential translation factor involved in several stages of eukaryotic translation and ribosome biogenesis. The nature of vital functions of ABCE1, however, remains unexplained. Here, we study the role of ABCE1 in human cell proliferation and its possible connection to translation. We show that ABCE1 depletion by siRNA results in a decreased rate of cell growth due to accumulation of cells in S phase, which is accompanied by inefficient DNA synthesis and reduced histone mRNA and protein levels. We infer that in addition to the role in general translation, ABCE1 is involved in histone biosynthesis and DNA replication and therefore is essential for normal S phase progression. In addition, we analyze whether ABCE1 is implicated in transcript-specific translation via its association with the eIF3 complex subunits known to control the synthesis of cell proliferation-related proteins. The expression levels of a few such targets regulated by eIF3A, however, were not consistently affected by ABCE1 depletion.

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Section: Discussionsupporting

confidence: 63%

Section: Abce1 Downregulation Impairs Cell Proliferation and Cell Cycmentioning

confidence: 97%

ABCE1 is essential for S phase progression in human cells

et al. 2016

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“…A severe histone reduction provokes strong replication defects, accumulation of cells in the S and G2 cell-cycle phases, and genetic instability (27,40). However, the subtle histone depletion used in our work has allowed us to analyze the transcriptional phenotypes caused by histone depletion without affecting cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

Jimeno-González

Payán-Bravo

Muñoz-Cabello

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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RNA polymerase II (RNAPII) transcription elongation is a highly regulated process that greatly influences mRNA levels as well as pre-mRNA splicing. Despite many studies in vitro, how chromatin modulates RNAPII elongation in vivo is still unclear. Here, we show that a decrease in the level of available canonical histones leads to more accessible chromatin with decreased levels of canonical histones and variants H2A.X and H2A.Z and increased levels of H3.3. With this altered chromatin structure, the RNAPII elongation rate increases, and the kinetics of pre-mRNA splicing is delayed with respect to RNAPII elongation. Consistent with the kinetic model of cotranscriptional splicing, the rapid RNAPII elongation induced by histone depletion promotes the skipping of variable exons in the CD44 gene. Indeed, a slowly elongating mutant of RNAPII was able to rescue this defect, indicating that the defective splicing induced by histone depletion is a direct consequence of the increased elongation rate. In addition, genome-wide analysis evidenced that histone reduction promotes widespread alterations in pre-mRNA processing, including intron retention and changes in alternative splicing. Our data demonstrate that premRNA splicing may be regulated by chromatin structure through the modulation of the RNAPII elongation rate. T he transcription process comprises several steps, including preinitiation complex formation, promoter escape, elongation, and termination (1). Recent reports indicate that elongation rates of RNA polymerase II (RNAPII) in mammals range from 0.5 to 4 kb/min, but which factors are responsible for these differences is still unclear (2-4). One obvious candidate for affecting transcription elongation is chromatin structure. The building block of chromatin is the nucleosome comprising 147 bp of DNA around a histone octamer formed by two H2A-H2B dimers and one H3-H4 tetramer. In vitro experiments have demonstrated that nucleosomes are a barrier for RNAPII transcription elongation (5, 6). We have reported that a nucleosome positioned in the body of a transcription unit impairs RNAPII progression in vivo (7). Furthermore, Weber et al. (8) have shown recently that RNAPII stalls in vivo at the entry site of essentially every transcribed nucleosome in Drosophila. Despite this evidence, it is still unclear whether changes in chromatin structure in different regions of a gene or between different genes can regulate the rate of transcription elongation.Transcription and splicing are coupled processes (9, 10). Splicing occurs cotranscriptionally, and multiple lines of evidence indicate that transcription elongation and splicing influence each other. On one hand, it has been suggested that splicing factors are recruited to the template by the transcription machinery (11, 12). On the other hand, the rate of RNAPII elongation influences splicing. The kinetic model proposes that a slow elongation rate facilitates weak splice-site recognition, promoting the inclusion of alternative exons (13, 14). However, recent studies have ex...

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“…U7 snRNA was detected by Northern blot analysis and U6 or U8 snRNA was detected as a control. accumulate in the cell (27). Another intriguing possibility is that an unidentified mechanism compensates for the 3′-end processing of histone mRNAs once a critical factor is abolished.…”

Section: Discussionmentioning

confidence: 99%

U7 small nuclear ribonucleoprotein represses histone gene transcription in cell cycle-arrested cells

Ideue¹,

Adachi

Naganuma³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Histone gene expression is tightly coordinated with DNA replication, as it is activated at the onset of S phase and suppressed at the end of S phase. Replication-dependent histone gene expression is precisely controlled at both transcriptional and posttranscriptional levels. U7 small nuclear ribonucleoprotein (U7 snRNP) is involved in the 3′-end processing of nonpolyadenylated histone mRNAs, which is required for S phase-specific gene expression. The present study reports a unique function of U7 snRNP in the repression of histone gene transcription under cell cycle-arrested conditions. Elimination of U7 snRNA with an antisense oligonucleotide in HeLa cells as well as in nontransformed human lung fibroblasts resulted in elevated levels of replication-dependent H1, H2A, H2B, H3, and H4 histone mRNAs but not of replication-independent H3F3B histone mRNA. An analogous effect was observed upon depletion of Lsm10, a component of the U7 snRNP-specific Sm ring, with siRNA. Pulse–chase experiments revealed that U7 snRNP acts to repress transcription without remarkably altering mRNA stability. Mass spectrometric analysis of the captured U7 snRNP from HeLa cell extracts identified heterogeneous nuclear (hn)RNP UL1 as a U7 snRNP interaction partner. Further knockdown and overexpression experiments revealed that hnRNP UL1 is responsible for U7 snRNP-dependent transcriptional repression of replication-dependent histone genes. Chromatin immunoprecipitation confirmed that hnRNP UL1 is recruited to the histone gene locus only when U7 snRNP is present. These findings support a unique mechanism of snRNP-mediated transcriptional control that restricts histone synthesis to S phase, thereby preventing the potentially toxic effects of histone synthesis at other times in the cell cycle.

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Knockdown of SLBP results in nuclear retention of histone mRNA

Cited by 91 publications

References 58 publications

ABCE1 is essential for S phase progression in human cells

ABCE1 is essential for S phase progression in human cells

Defective histone supply causes changes in RNA polymerase II elongation rate and cotranscriptional pre-mRNA splicing

U7 small nuclear ribonucleoprotein represses histone gene transcription in cell cycle-arrested cells

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