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1.
Nature ; 627(8002): 212-220, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38355801

RESUMO

Circular RNAs (circRNAs), which are increasingly being implicated in a variety of functions in normal and cancerous cells1-5, are formed by back-splicing of precursor mRNAs in the nucleus6-10. circRNAs are predominantly localized in the cytoplasm, indicating that they must be exported from the nucleus. Here we identify a pathway that is specific for the nuclear export of circular RNA. This pathway requires Ran-GTP, exportin-2 and IGF2BP1. Enhancing the nuclear Ran-GTP gradient by depletion or chemical inhibition of the major protein exporter CRM1 selectively increases the nuclear export of circRNAs, while reducing the nuclear Ran-GTP gradient selectively blocks circRNA export. Depletion or knockout of exportin-2 specifically inhibits nuclear export of circRNA. Analysis of nuclear circRNA-binding proteins reveals that interaction between IGF2BP1 and circRNA is enhanced by Ran-GTP. The formation of circRNA export complexes in the nucleus is promoted by Ran-GTP through its interactions with exportin-2, circRNA and IGF2BP1. Our findings demonstrate that adaptors such as IGF2BP1 that bind directly to circular RNAs recruit Ran-GTP and exportin-2 to export circRNAs in a mechanism that is analogous to protein export, rather than mRNA export.


Assuntos
Transporte Ativo do Núcleo Celular , Núcleo Celular , Transporte de RNA , RNA Circular , Transporte Ativo do Núcleo Celular/fisiologia , Núcleo Celular/metabolismo , Guanosina Trifosfato/metabolismo , Carioferinas/antagonistas & inibidores , Carioferinas/deficiência , Carioferinas/genética , Carioferinas/metabolismo , Proteínas Nucleares/metabolismo , Proteína ran de Ligação ao GTP/metabolismo , RNA Circular/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína Exportina 1/metabolismo , Transporte Proteico
2.
Mol Cell ; 81(10): 2183-2200.e13, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34019788

RESUMO

To separate causal effects of histone acetylation on chromatin accessibility and transcriptional output, we used integrated epigenomic and transcriptomic analyses following acute inhibition of major cellular lysine acetyltransferases P300 and CBP in hematological malignancies. We found that catalytic P300/CBP inhibition dynamically perturbs steady-state acetylation kinetics and suppresses oncogenic transcriptional networks in the absence of changes to chromatin accessibility. CRISPR-Cas9 screening identified NCOR1 and HDAC3 transcriptional co-repressors as the principal antagonists of P300/CBP by counteracting acetylation turnover kinetics. Finally, deacetylation of H3K27 provides nucleation sites for reciprocal methylation switching, a feature that can be exploited therapeutically by concomitant KDM6A and P300/CBP inhibition. Overall, this study indicates that the steady-state histone acetylation-methylation equilibrium functions as a molecular rheostat governing cellular transcription that is amenable to therapeutic exploitation as an anti-cancer regimen.


Assuntos
Biocatálise , Histonas/metabolismo , Oncogenes , Transcrição Gênica , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Linhagem Celular , Cromatina/metabolismo , Proteínas Correpressoras/metabolismo , Sequência Conservada , Evolução Molecular , Redes Reguladoras de Genes , Genoma , Histona Desacetilases/metabolismo , Humanos , Cinética , Metilação , Modelos Biológicos , RNA Polimerase II/metabolismo
3.
Nat Rev Mol Cell Biol ; 16(7): 431-42, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26081607

RESUMO

Nuclear export of mRNAs is a crucial step in the regulation of gene expression, linking transcription in the nucleus to translation in the cytoplasm. Although important components of the mRNA export machinery are well characterized, such as transcription-export complexes TREX and TREX-2, recent work has shown that, in some instances, mammalian mRNA export can be selective and can regulate crucial biological processes such as DNA repair, gene expression, maintenance of pluripotency, haematopoiesis, proliferation and cell survival. Such findings show that mRNA export is an unexpected, yet potentially important, mechanism for the control of gene expression and of the mammalian transcriptome.


Assuntos
Transporte Ativo do Núcleo Celular , Regulação da Expressão Gênica , Mamíferos/genética , RNA Mensageiro/metabolismo , Animais , Citoplasma/metabolismo , Exodesoxirribonucleases/metabolismo , Humanos , Mamíferos/metabolismo , Neoplasias/metabolismo , Ribonucleoproteínas/metabolismo
5.
Hum Mol Genet ; 31(3): 362-375, 2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-34494102

RESUMO

The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here, we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings' neurological disorder.


Assuntos
Deficiência Intelectual , Microcefalia , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética
6.
Mol Cell ; 61(4): 496-505, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26895423

RESUMO

It is emerging that the pathways that process newly transcribed RNA molecules also regulate the response to DNA damage at multiple levels. Here, we discuss recent insights into how RNA processing pathways participate in DNA damage recognition, signaling, and repair, selectively influence the expression of genome-stabilizing proteins, and resolve deleterious DNA/RNA hybrids (R-loops) formed during transcription and RNA processing. The importance of these pathways for the DNA damage response (DDR) is underscored by the growing appreciation that defects in these regulatory connections may be connected to the genome instability involved in several human diseases, including cancer.


Assuntos
Genoma Humano , Instabilidade Genômica , Processamento Pós-Transcricional do RNA , RNA/metabolismo , Dano ao DNA , Reparo do DNA , Humanos , Transdução de Sinais
7.
Trends Genet ; 34(4): 279-290, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29329719

RESUMO

Splicing and nuclear export of mRNA are critical steps in the gene expression pathway. While RNA processing factors can perform general, essential functions for intron removal and bulk export of mRNA, emerging evidence highlights that the core RNA splicing and export machineries also display regulatory potential. Here, we discuss recent insights into how this regulatory potential can selectively alter gene expression and regulate important biological processes. We also highlight the participation of RNA processing pathways in the cellular response to DNA damage at multiple levels. These findings have important implications for the contribution of selective mRNA processing and export to the development of human cancers and neurodegenerative disorders.


Assuntos
Carcinogênese/genética , Neoplasias/genética , Doenças Neurodegenerativas/genética , Splicing de RNA , RNA Mensageiro/genética , Spliceossomos/genética , Transporte Ativo do Núcleo Celular , Carcinogênese/metabolismo , Carcinogênese/patologia , Citoplasma/genética , Citoplasma/metabolismo , Dano ao DNA , Células Eucarióticas/metabolismo , Genoma Humano , Instabilidade Genômica , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , RNA Mensageiro/metabolismo , RNA Nuclear Pequeno/genética , RNA Nuclear Pequeno/metabolismo , Spliceossomos/metabolismo
8.
Mol Cell ; 51(6): 737-50, 2013 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-24074953

RESUMO

Messenger RNA (mRNA) export from the nucleus is essential for eukaryotic gene expression. Here we identify a transcript-selective nuclear export mechanism affecting certain human transcripts, enriched for functions in genome duplication and repair, controlled by inositol polyphosphate multikinase (IPMK), an enzyme catalyzing inositol polyphosphate and phosphoinositide turnover. We studied transcripts encoding RAD51, a protein essential for DNA repair by homologous recombination (HR), to characterize the mechanism underlying IPMK-regulated mRNA export. IPMK depletion or catalytic inactivation selectively decreases RAD51 protein abundance and the nuclear export of RAD51 mRNA, thereby impairing HR. Recognition of a sequence motif in the untranslated region of RAD51 transcripts by the mRNA export factor ALY requires IPMK. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), an IPMK product, restores ALY recognition in IPMK-depleted cell extracts, suggesting a mechanism underlying transcript selection. Our findings implicate IPMK in a transcript-selective mRNA export pathway controlled by phosphoinositide turnover that preserves genome integrity in humans.


Assuntos
Transporte Ativo do Núcleo Celular/genética , Instabilidade Genômica , Fosfotransferases (Aceptor do Grupo Álcool)/genética , RNA Mensageiro/genética , Linhagem Celular Tumoral , Núcleo Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genoma Humano , Recombinação Homóloga/genética , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , Fosforilação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais
9.
Semin Cell Dev Biol ; 75: 70-77, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28866329

RESUMO

Export of protein-coding and non-coding RNA molecules from the nucleus to the cytoplasm is critical for gene expression. This necessitates the continuous transport of RNA species of different size, shape and function through nuclear pore complexes via export receptors and adaptor proteins. Here, we provide an overview of the major RNA export pathways in humans, highlighting the similarities and differences between each. Its importance is underscored by the growing appreciation that deregulation of RNA export pathways is associated with human diseases like cancer.


Assuntos
Núcleo Celular/metabolismo , Citoplasma/metabolismo , Isoformas de RNA/metabolismo , RNA/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Humanos , Modelos Biológicos , RNA/genética , Isoformas de RNA/genética , Transporte de RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
10.
Nucleic Acids Res ; 42(8): 5059-71, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24510098

RESUMO

The nuclear phase of the gene expression pathway culminates in the export of mature messenger RNAs (mRNAs) to the cytoplasm through nuclear pore complexes. GANP (germinal- centre associated nuclear protein) promotes the transfer of mRNAs bound to the transport factor NXF1 to nuclear pore complexes. Here, we demonstrate that GANP, subunit of the TRanscription-EXport-2 (TREX-2) mRNA export complex, promotes selective nuclear export of a specific subset of mRNAs whose transport depends on NXF1. Genome-wide gene expression profiling showed that half of the transcripts whose nuclear export was impaired following NXF1 depletion also showed reduced export when GANP was depleted. GANP-dependent transcripts were highly expressed, yet short-lived, and were highly enriched in those encoding central components of the gene expression machinery such as RNA synthesis and processing factors. After injection into Xenopus oocyte nuclei, representative GANP-dependent transcripts showed faster nuclear export kinetics than representative transcripts that were not influenced by GANP depletion. We propose that GANP promotes the nuclear export of specific classes of mRNAs that may facilitate rapid changes in gene expression.


Assuntos
Acetiltransferases/fisiologia , Núcleo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , RNA Mensageiro/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Linhagem Celular Tumoral , Humanos , Proteínas de Transporte Nucleocitoplasmático/fisiologia , RNA Mensageiro/classificação , Proteínas de Ligação a RNA/fisiologia , Xenopus
11.
Nucleic Acids Res ; 40(10): 4562-73, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22307388

RESUMO

Export of messenger RNA (mRNA) from the nucleus to the cytoplasm is a critical step in the gene expression pathway of eukaryotic cells. Here, we report the functional and structural characterization of the mammalian TREX-2 complex and show how it links transcription/processing with nuclear mRNA export. Mammalian TREX-2 is based on a germinal-centre associated nuclear protein (GANP) scaffold to which ENY2, PCID2 and centrins bind and depletion of any of these components inhibits mRNA export. The crystal structure of the GANP:ENY2 complex shows that two ENY2 chains interact directly with GANP, but they have different orientations from those observed on yeast Sac3. GANP is required to recruit ENY2 to nuclear pore complexes (NPCs), but ENY2 is not necessary to recruit GANP, which requires both its CID and MCM3AP domains, together with nucleoporin Nup153. GANP and ENY2 associate with RNA polymerase II and inhibition of mRNA processing redistributes GANP from NPCs into nuclear foci indicating that mammalian TREX-2 is associated with transcription. Thus, we implicate TREX-2 as an integral component of the mammalian mRNA export machinery where it links transcription and nuclear export by facilitating the transfer of mature mRNPs from the nuclear interior to NPCs.


Assuntos
Acetiltransferases/química , Núcleo Celular/genética , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , RNA Mensageiro/metabolismo , Transcrição Gênica , Acetiltransferases/análise , Acetiltransferases/metabolismo , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Núcleo Celular/metabolismo , Cristalografia por Raios X , Exodesoxirribonucleases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Moleculares , Dados de Sequência Molecular , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas Nucleares/análise , Fosfoproteínas/metabolismo , Transporte de RNA , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
12.
Nat Commun ; 13(1): 1100, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35232962

RESUMO

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.


Assuntos
Melanoma , Proteínas Proto-Oncogênicas B-raf , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Terapia de Alvo Molecular , Mutação , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , RNA Mensageiro/uso terapêutico
13.
Nat Rev Cancer ; 21(1): 22-36, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33082563

RESUMO

While the processing of mRNA is essential for gene expression, recent findings have highlighted that RNA processing is systematically altered in cancer. Mutations in RNA splicing factor genes and the shortening of 3' untranslated regions are widely observed. Moreover, evidence is accumulating that other types of RNAs, including circular RNAs, can contribute to tumorigenesis. In this Review, we highlight how altered processing or activity of coding and non-coding RNAs contributes to cancer. We introduce the regulation of gene expression by coding and non-coding RNA and discuss both established roles (microRNAs and long non-coding RNAs) and emerging roles (selective mRNA processing and circular RNAs) for RNAs, highlighting the potential mechanisms by which these RNA subtypes contribute to cancer. The widespread alteration of coding and non-coding RNA demonstrates that altered RNA biogenesis contributes to multiple hallmarks of cancer.


Assuntos
Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Neoplasias/patologia , Processamento Pós-Transcricional do RNA , RNA/genética , Animais , Carcinogênese/genética , Humanos , MicroRNAs/genética , Neoplasias/genética , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética
14.
Blood Adv ; 4(7): 1270-1283, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32236527

RESUMO

In eukaryotic cells, messenger RNA (mRNA) molecules are exported from the nucleus to the cytoplasm, where they are translated. The highly conserved protein nuclear RNA export factor1 (Nxf1) is an important mediator of this process. Although studies in yeast and in human cell lines have shed light on the biochemical mechanisms of Nxf1 function, its contribution to mammalian physiology is less clear. Several groups have identified recurrent NXF1 mutations in chronic lymphocytic leukemia (CLL), placing it alongside several RNA-metabolism factors (including SF3B1, XPO, RPS15) whose dysregulation is thought to contribute to CLL pathogenesis. We report here an allelic series of germline point mutations in murine Nxf1. Mice heterozygous for these loss-of-function Nxf1 mutations exhibit thrombocytopenia and lymphopenia, together with milder hematological defects. This is primarily caused by cell-intrinsic defects in the survival of platelets and peripheral lymphocytes, which are sensitized to intrinsic apoptosis. In contrast, Nxf1 mutations have almost no effect on red blood cell homeostasis. Comparative transcriptome analysis of platelets, lymphocytes, and erythrocytes from Nxf1-mutant mice shows that, in response to impaired Nxf1 function, the cytoplasmic representation of transcripts encoding regulators of RNA metabolism is altered in a unique, lineage-specific way. Thus, blood cell lineages exhibit differential requirements for Nxf1-mediated global mRNA export.


Assuntos
Linfopenia , Trombocitopenia , Animais , Células Germinativas , Linfopenia/genética , Camundongos , Mutação , Proteínas de Transporte Nucleocitoplasmático/genética , RNA Viral , Proteínas de Ligação a RNA/genética , Trombocitopenia/genética
16.
Nat Struct Mol Biol ; 26(10): 930-940, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570875

RESUMO

Studies of spliceosomal interactions are challenging due to their dynamic nature. Here we used spliceosome iCLIP, which immunoprecipitates SmB along with small nuclear ribonucleoprotein particles and auxiliary RNA binding proteins, to map spliceosome engagement with pre-messenger RNAs in human cell lines. This revealed seven peaks of spliceosomal crosslinking around branchpoints (BPs) and splice sites. We identified RNA binding proteins that crosslink to each peak, including known and candidate splicing factors. Moreover, we detected the use of over 40,000 BPs with strong sequence consensus and structural accessibility, which align well to nearby crosslinking peaks. We show how the position and strength of BPs affect the crosslinking patterns of spliceosomal factors, which bind more efficiently upstream of strong or proximally located BPs and downstream of weak or distally located BPs. These insights exemplify spliceosome iCLIP as a broadly applicable method for transcriptomic studies of splicing mechanisms.


Assuntos
Precursores de RNA/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Spliceossomos/metabolismo , Linhagem Celular , Humanos , Sítios de Splice de RNA , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo
17.
Cell Rep ; 20(5): 1229-1241, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768205

RESUMO

Alternative splicing is a critical determinant of genome complexity and, by implication, is assumed to engender proteomic diversity. This notion has not been experimentally tested in a targeted, quantitative manner. Here, we have developed an integrative approach to ask whether perturbations in mRNA splicing patterns alter the composition of the proteome. We integrate RNA sequencing (RNA-seq) (to comprehensively report intron retention, differential transcript usage, and gene expression) with a data-independent acquisition (DIA) method, SWATH-MS (sequential window acquisition of all theoretical spectra-mass spectrometry), to capture an unbiased, quantitative snapshot of the impact of constitutive and alternative splicing events on the proteome. Whereas intron retention is accompanied by decreased protein abundance, alterations in differential transcript usage and gene expression alter protein abundance proportionate to transcript levels. Our findings illustrate how RNA splicing links isoform expression in the human transcriptome with proteomic diversity and provides a foundation for studying perturbations associated with human diseases.


Assuntos
Processamento Alternativo/fisiologia , Proteoma/biossíntese , Proteoma/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Feminino , Humanos , Masculino
19.
Genome Biol ; 16: 201, 2015 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-26392272

RESUMO

BACKGROUND: Sequential assembly of the human spliceosome on RNA transcripts regulates splicing across the human transcriptome. The core spliceosome component PRPF8 is essential for spliceosome assembly through its participation in ribonucleoprotein (RNP) complexes for splice-site recognition, branch-point formation and catalysis. PRPF8 deficiency is linked to human diseases like retinitis pigmentosa or myeloid neoplasia, but its genome-wide effects on constitutive and alternative splicing remain unclear. RESULTS: Here, we show that alterations in RNA splicing patterns across the human transcriptome that occur in conditions of restricted cellular PRPF8 abundance are defined by the altered splicing of introns with weak 5' splice sites. iCLIP of spliceosome components reveals that PRPF8 depletion decreases RNP complex formation at most splice sites in exon-intron junctions throughout the genome. However, impaired splicing affects only a subset of human transcripts, enriched for mitotic cell cycle factors, leading to mitotic arrest. Preferentially retained introns and differentially used exons in the affected genes contain weak 5' splice sites, but are otherwise indistinguishable from adjacent spliced introns. Experimental enhancement of splice-site strength in mini-gene constructs overcomes the effects of PRPF8 depletion on the kinetics and fidelity of splicing during transcription. CONCLUSIONS: Competition for PRPF8 availability alters the transcription-coupled splicing of RNAs in which weak 5' splice sites predominate, enabling diversification of human gene expression during biological processes like mitosis. Our findings exemplify the regulatory potential of changes in the core spliceosome machinery, which may be relevant to slow-onset human genetic diseases linked to PRPF8 deficiency.


Assuntos
Processamento Alternativo/genética , Proteínas de Ligação a RNA/genética , Retinose Pigmentar/genética , Transcriptoma/genética , Éxons/genética , Genoma , Humanos , Íntrons/genética , Mutação , Sítios de Splice de RNA , RNA Mensageiro/genética , Retinose Pigmentar/patologia , Ribonucleoproteínas/genética , Spliceossomos/genética
20.
J Mol Biol ; 406(3): 355-61, 2011 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-21195085

RESUMO

MCM3 acetylase (MCM3AP) and germinal-centre associated nuclear protein (GANP) are transcribed from the same locus and are therefore confused in databases because the MCM3 acetylase DNA sequence is contained entirely within the much larger GANP sequence and the entire MCM3AP sequence is identical to the carboxy terminus of GANP. Thus, the MCM3AP and GANP genes are read in the same reading frame and MCM3AP is an N-terminally truncated region of GANP. However, we show here that MCM3AP and GANP are different proteins, occupying different locations in the cell and transcribed from different promoters. Intriguingly, a promoter for MCM3AP lies within an intron of GANP. This report is an interesting example in nature of two separate gene products from the same locus that perform two entirely different functions in the cell. Therefore, to avoid further confusion, they should now be referred to as separate but overlapping genes.


Assuntos
Acetiltransferases/genética , Homologia de Genes , Bases de Dados Genéticas , Loci Gênicos , Genoma Humano , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Íntrons , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Análise de Sequência de DNA , Transcrição Gênica
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