Abstract:
:Genotoxic stress induces alternative splicing of the oncogene MDM2 generating MDM2-ALT1, an isoform attributed with tumorigenic properties. However, the mechanisms underlying this event remain unclear. Here we explore MDM2 splicing regulation by utilizing a novel minigene that mimics endogenous MDM2 splicing in response to UV and cisplatinum-induced DNA damage. We report that exon 11 is necessary and sufficient for the damage-specific alternative splicing of the MDM2 minigene and that the splicing factor SRSF1 binds exon 11 at evolutionarily conserved sites. Interestingly, mutations disrupting this interaction proved sufficient to abolish the stress-induced alternative splicing of the MDM2 minigene. Furthermore, SRSF1 overexpression promoted exclusion of exon 11, while its siRNA-mediated knockdown prevented the stress-induced alternative splicing of endogenous MDM2. Additionally, we observed elevated SRSF1 levels under stress and in tumors correlating with the expression of MDM2-ALT1. Notably, we demonstrate that MDM2-ALT1 splicing can be blocked by targeting SRSF1 sites on exon 11 using antisense oligonucleotides. These results present conclusive evidence supporting a negative role for SRSF1 in MDM2 alternative splicing. Importantly, we define for the first time, a clear-cut mechanism for the regulation of damage-induced MDM2 splicing and present potential strategies for manipulating MDM2 expression via splicing modulation.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Comiskey DF Jr,Jacob AG,Singh RK,Tapia-Santos AS,Chandler DSdoi
10.1093/nar/gkv223subject
Has Abstractpub_date
2015-04-30 00:00:00pages
4202-18issue
8eissn
0305-1048issn
1362-4962pii
gkv223journal_volume
43pub_type
杂志文章abstract::During translation initiation, eukaryotic initiation factor 2 (eIF2) delivers the Met-tRNA to the 40S ribosomal subunit to locate the initiation codon (AUGi) of mRNA during the scanning process. Stress-induced eIF2 phosphorylation leads to a general blockade of translation initiation and represents a key antiviral pat...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkw172
更新日期:2016-05-19 00:00:00
abstract::Electrophoresis of the mixture of proteins from purified snRNPs U1, U2, U4/U6 and U5 on SDS-polyacrylamide gels that had been allowed to polymerise in the presence of high TEMED concentrations have revealed the presence of proteins in the snRNPs that previously had eluded detection. The most striking case is that of p...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/18.22.6475
更新日期:1990-11-25 00:00:00
abstract::Current knowledge of parameters affecting RNA stability is very restricted in plants. Here we investigated factors which might contribute to the stability of a particular plant messenger RNA. To this end, insertion and deletion mutants were made in two different exons and an intron of the transcribed region of a well ...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/18.10.2917
更新日期:1990-05-25 00:00:00
abstract::Two residues are invariant in all bZip basic regions: asparagine -18 and arginine -10 (we define the first leucine of the leucine zipper of GCN4 as +1). X-ray structures of two specific GCN4-DNA complexes (Ellenberger et al., Cell, 71, 1223-1237, 1992; König & Richmond, J. Mol. Biol., 233, 139-154, 1993) demonstrate t...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/22.21.4395
更新日期:1994-10-25 00:00:00
abstract::We have characterized triple-helix-mediated inhibition of an artificial bacteriophage promoter with respect to relief of inhibition by incoming RNA polymerases that initiate upstream or downstream from the operator sequence. Whereas oligonucleotide-directed triple-helix formation inhibits the test promoter, promoter a...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/21.17.4055
更新日期:1993-08-25 00:00:00
abstract::We present MultiGO, a web-enabled tool for the identification of biologically relevant gene sets from hierarchically clustered gene expression trees (http://ekhidna.biocenter.helsinki.fi/poxo/multigo). High-throughput gene expression measuring techniques, such as microarrays, are nowadays often used to monitor the exp...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkl694
更新日期:2006-01-01 00:00:00
abstract::Proteins perform biological functions through cascading interactions with each other by forming protein complexes. As a result, interactions among proteins, called protein-protein interactions (PPIs) are not completely free from selection constraint during evolution. Therefore, the identification and analysis of PPI c...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gky378
更新日期:2018-07-02 00:00:00
abstract::GC content bias describes the dependence between fragment count (read coverage) and GC content found in Illumina sequencing data. This bias can dominate the signal of interest for analyses that focus on measuring fragment abundance within a genome, such as copy number estimation (DNA-seq). The bias is not consistent b...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gks001
更新日期:2012-05-01 00:00:00
abstract::We show that the cAMP receptor protein (Crp) binds to DNA as several different conformers. This situation has precluded discovering a high correlation between any sequence property and binding affinity for proteins that bend DNA. Experimentally quantified affinities of Synechocystis sp. PCC 6803 cAMP receptor protein ...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkr369
更新日期:2011-08-01 00:00:00
abstract::The potent anticancer drug actinomycin D (ActD) functions by intercalating into DNA at GpC sites, thereby interrupting essential biological processes including replication and transcription. Certain neurological diseases are correlated with the expansion of (CGG)n trinucleotide sequences, which contain many contiguous...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkt084
更新日期:2013-04-01 00:00:00
abstract::It is a routine task in metabolic engineering to introduce multicomponent pathways into a heterologous host for production of metabolites. However, this process sometimes may take weeks to months due to the lack of standardized genetic tools. Here, we present a method for the design and construction of biological part...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkv464
更新日期:2015-07-27 00:00:00
abstract::Lytic infection with polyoma virus leads in Go-arrested primary mouse kidney cell cultures to a mitotic host response. In the present work we focused our attention on cellular RNA synthesis shortly after onset of polyoma T-antigen synthesis. Onset of polyoma-induced stimulation of 45S pre-rRNA synthesis was determined...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/11.19.6611
更新日期:1983-10-11 00:00:00
abstract::We have amplified the large subunit ribosomal DNA (LSUrDNA) of the 12 described Naegleria spp. and of 34 other Naegleria lineages that might be distinct species. Two strains yielded a product that is longer than 3 kb, which is the length of the LSUrDNA of all described Naegleria spp. Sequencing data revealed that the ...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/26.2.456
更新日期:1998-01-15 00:00:00
abstract::We have reported that an upstream stimulatory factor (USF) binding site is functional in transcription of the heme oxygenase-1 gene. In this study, we examined the role of USF in the induced state. By transient expression analyses with the chloramphenicol acetyl-transferase gene, we found that the USF binding site pla...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/24.15.2959
更新日期:1996-08-01 00:00:00
abstract::MicroRNAs (miRNAs) are small RNAs ∼22 nt in length that are involved in the regulation of a variety of physiological and pathological processes. Advances in high-throughput small RNA sequencing (smRNA-seq), one of the next-generation sequencing applications, have reshaped the miRNA research landscape. In this study, w...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gks1238
更新日期:2013-01-01 00:00:00
abstract::A very mild and efficient procedure has been developed for the preparation of C-5 substituted deoxyuridines. The substituent carries a masked primary aliphatic amino group. These compounds are readily converted into their phosphoramidites and can be used to prepare oligonucleotides carrying one or more aliphatic amino...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/15.12.4857
更新日期:1987-06-25 00:00:00
abstract::Mitotic chromosome structure is pivotal to cell division but difficult to observe in fine detail using conventional methods. DNA catenation has been implicated in both sister chromatid cohesion and chromosome condensation, but has never been observed directly. We have used a lab-on-a-chip microfluidic device and fluor...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gks931
更新日期:2012-12-01 00:00:00
abstract::Embryonic stem cells (ESCs) and meiosis are featured by relatively higher frequent homologous recombination associated with DNA double strand breaks (DSB) repair. Here, we show that Pold3 plays important roles in DSB repair, telomere maintenance and genomic stability of both ESCs and spermatocytes in mice. By attempti...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gky098
更新日期:2018-04-20 00:00:00
abstract::The nucleotide sequences of the LTRs and their adjacent regions from 19 type C and one type B retrovirus were compared. Salient features are: (a) The R regions in the genomes of most of the type C retroviruses begin with GC and end with CA. (b) The mammalian type C retroviruses have a polyadenylation signal "AATAAA" i...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/12.4.1767
更新日期:1984-02-24 00:00:00
abstract::In vivo footprinting experiments, augmented with gel shift and transfection analyses suggest that activation of the CYP1A1 gene by aryl hydrocarbons may be a multicomponent process. During the first 30 minutes of exposure to aryl hydrocarbon carcinogens and environmental contaminants, in vivo footprints appear at nine...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/22.9.1741
更新日期:1994-05-11 00:00:00
abstract::We have recently described three group I introns inserted into a single gene, orf142, of the staphylococcal bacteriophage Twort and suggested the presence of at least two additional self-splicing introns in this phage genome. Here we report that two previously uncharacterized introns, 429 and 1087 nt in length, interr...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/30.9.1935
更新日期:2002-05-01 00:00:00
abstract::In two-colour microarrays, the ratio of signal intensities of two co-hybridized samples is used as a relative measure of gene expression. Ratio-based analysis becomes complicated and inefficient in multi-class comparisons. We therefore investigated the validity of an intensity-based analysis procedure. To this end, tw...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gnh038
更新日期:2004-02-24 00:00:00
abstract::Stacking self-association equilibria in aqueous solutions of m3uridine, m34,2',3',5'uridine, 2'-deoxyuridine, m13,4,4cytosine, m14,4,4,5cytosine, s2cytidine and s4thymidine were studied at various temperatures by vapour-pressure osmometry. Equilibrium constants Kst's were computed on the assumption of the isodesmic mo...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/3.5.1295
更新日期:1976-05-01 00:00:00
abstract::The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) land...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkw1208
更新日期:2017-03-17 00:00:00
abstract::Analyses of secondary structures proposed for ribosomal RNA's show that, of the different kinds of base pairs directly adjoining the ends of postulated double-helical regions, only A-G with A at the 5' end significantly exceeds the number expected for a random base distribution. An A(syn)-G(trans) hydrogen-bonded base...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/10.8.2701
更新日期:1982-04-24 00:00:00
abstract::The 5'- and 3'-untranslated regions (5'- and 3'-UTRs) of eukaryotic mRNAs are known to play a crucial role in post-transcriptional regulation of gene expression modulating nucleo-cytoplasmic mRNA transport, translation efficiency, subcellular localization and stability. UTRdb is a specialized database of 5' and 3' unt...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/30.1.335
更新日期:2002-01-01 00:00:00
abstract::The replication control circuit of the FII plasmids R1, R100 and R6-5 involves a small untranslated RNA molecule of about 93 nucleotides. This RNA, designated CopA RNA in plasmid R1, acts in vivo as a post-transcriptional inhibitor of the expression of the RepA protein whose synthesis is required for each round of pla...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/14.6.2523
更新日期:1986-03-25 00:00:00
abstract::The Human Genome Project has facilitated the sequencing of many species, yet the current Sanger method is too expensive, labor intensive and time consuming to accomplish medical resequencing of human genomes en masse. Of the 'next-generation' technologies, cyclic reversible termination (CRT) is a promising method with...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkm689
更新日期:2007-01-01 00:00:00
abstract::Poly(ADP-ribosyl)ation is involved in numerous bio-logical processes including DNA repair, transcription and cell death. Cellular levels of poly(ADP-ribose) (PAR) are regulated by PAR polymerases (PARPs) and the degrading enzyme PAR glycohydrolase (PARG), controlling the cell fate decision between life and death in re...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gku505
更新日期:2014-07-01 00:00:00
abstract::Organisms exposed to reactive oxygen species, generated endogenously during respiration or by environmental conditions, undergo oxidative stress. Stress response can either repair the damage or activate one of the programmed cell death (PCD) mechanisms, for example apoptosis, and finally end in cell death. One strikin...
journal_title:Nucleic acids research
pub_type: 杂志文章
doi:10.1093/nar/gkm1100
更新日期:2008-05-01 00:00:00