Article
NELF interacts with CBC and participates in 3' end processing of replication-dependent histone mRNAs.
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama, Kanagawa 226-8501, Japan.
Molecular Cell (impact factor:
14.18).
06/2007;
26(3):349-65.
DOI:10.1016/j.molcel.2007.04.011
Source: PubMed
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Citations (0)
- Cited In (4)
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Article: Insights into the function of the human P-TEFb component CDK9 in the regulation of chromatin modifications and co-transcriptional mRNA processing.
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ABSTRACT: Cyclin-dependent kinase-9 (CDK9) was originally characterized as a transcription elongation factor which regulates RNA Polymerase II (RNAPII) activity following transcriptional initiation. However, recent evidence from a number of studies have shown that CDK9 plays an important role in regulating not only RNAPII activity but also co-transcriptional histone modification and mRNA processing events such as splicing and 3' end processing. Importantly, our previous work and the work presented here demonstrate that CDK9 functions to guide a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3. This function appears to be dependent upon not only the phosphorylation of the RNA Polymerase II C-terminal domain but also upon other CDK9 targets such as the Suppressor of Ty Homolog-5 (SUPT5H), Negative Elongation Factor-E (NELF-E) and probably the human Rad6 homolog UBE2A. We provide a working model by which CDK9 may control co-transcriptional replication-dependent histone mRNA 3' end processing in an H2Bub1 and H3K4me3-dependent manner and uncover new and important differences between the functions of human CDK9 and its yeast counterparts Ctk1 and Bur1.Cell cycle (Georgetown, Tex.) 11/2009; 8(22):3636-42. · 5.36 Impact Factor -
Article: Molecular mechanisms of eukaryotic pre-mRNA 3' end processing regulation.
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ABSTRACT: Messenger RNA (mRNA) 3' end formation is a nuclear process through which all eukaryotic primary transcripts are endonucleolytically cleaved and most of them acquire a poly(A) tail. This process, which consists in the recognition of defined poly(A) signals of the pre-mRNAs by a large cleavage/polyadenylation machinery, plays a critical role in gene expression. Indeed, the poly(A) tail of a mature mRNA is essential for its functions, including stability, translocation to the cytoplasm and translation. In addition, this process serves as a bridge in the network connecting the different transcription, capping, splicing and export machineries. It also participates in the quantitative and qualitative regulation of gene expression in a variety of biological processes through the selection of single or alternative poly(A) signals in transcription units. A large number of protein factors associates with this machinery to regulate the efficiency and specificity of this process and to mediate its interaction with other nuclear events. Here, we review the eukaryotic 3' end processing machineries as well as the comprehensive set of regulatory factors and discuss the different molecular mechanisms of 3' end processing regulation by proposing several overlapping models of regulation.Nucleic Acids Research 05/2010; 38(9):2757-74. · 8.03 Impact Factor -
Article: Systems-wide RNAi analysis of CASP8AP2/FLASH shows transcriptional deregulation of the replication-dependent histone genes and extensive effects on the transcriptome of colorectal cancer cells.
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ABSTRACT: Colorectal carcinomas (CRC) carry massive genetic and transcriptional alterations that influence multiple cellular pathways. The study of proteins whose loss-of-function (LOF) alters the growth of CRC cells can be used to further understand the cellular processes cancer cells depend upon for survival. A small-scale RNAi screen of ~400 genes conducted in SW480 CRC cells identified several candidate genes as required for the viability of CRC cells, most prominently CASP8AP2/FLASH. To understand the function of this gene in maintaining the viability of CRC cells in an unbiased manner, we generated gene specific expression profiles following RNAi. Silencing of CASP8AP2/FLASH resulted in altered expression of over 2500 genes enriched for genes associated with cellular growth and proliferation. Loss of CASP8AP2/FLASH function was significantly associated with altered transcription of the genes encoding the replication-dependent histone proteins as a result of the expression of the non-canonical polyA variants of these transcripts. Silencing of CASP8AP2/FLASH also mediated enrichment of changes in the expression of targets of the NFκB and MYC transcription factors. These findings were confirmed by whole transcriptome analysis of CASP8AP2/FLASH silenced cells at multiple time points. Finally, we identified and validated that CASP8AP2/FLASH LOF increases the expression of neurofilament heavy polypeptide (NEFH), a protein recently linked to regulation of the AKT1/ß-catenin pathway. We have used unbiased RNAi based approaches to identify and characterize the function of CASP8AP2/FLASH, a protein not previously reported as required for cell survival. This study further defines the role CASP8AP2/FLASH plays in the regulating expression of the replication-dependent histones and shows that its LOF results in broad and reproducible effects on the transcriptome of colorectal cancer cells including the induction of expression of the recently described tumor suppressor gene NEFH.Molecular Cancer 01/2012; 11:1. · 3.99 Impact Factor
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Keywords
CBC
CBC causes aberrant production
cleavage bodies
coordinates different mRNA processing steps
forms distinct intranuclear foci
four subunit transcription elongation factor
histone gene loci
histone stem-loop binding protein
Negative elongation factor
NELF
NELF interacts
neurological disorders
nuclear cap binding complex
numerous diseases
roles
Strikingly
surprising role