Publication Date:
2012-03-27
Description:
Alternative messenger RNA splicing is the main reason that vast mammalian proteomic complexity can be achieved with a limited number of genes. Splicing is physically and functionally coupled to transcription, and is greatly affected by the rate of transcript elongation. As the nascent pre-mRNA emerges from transcribing RNA polymerase II (RNAPII), it is assembled into a messenger ribonucleoprotein (mRNP) particle; this is the functional form of the nascent pre-mRNA and determines the fate of the mature transcript. However, factors that connect the transcribing polymerase with the mRNP particle and help to integrate transcript elongation with mRNA splicing remain unclear. Here we characterize the human interactome of chromatin-associated mRNP particles. This led us to identify deleted in breast cancer 1 (DBC1) and ZNF326 (which we call ZNF-protein interacting with nuclear mRNPs and DBC1 (ZIRD)) as subunits of a novel protein complex--named DBIRD--that binds directly to RNAPII. DBIRD regulates alternative splicing of a large set of exons embedded in (A + T)-rich DNA, and is present at the affected exons. RNA-interference-mediated DBIRD depletion results in region-specific decreases in transcript elongation, particularly across areas encompassing affected exons. Together, these data indicate that the DBIRD complex acts at the interface between mRNP particles and RNAPII, integrating transcript elongation with the regulation of alternative splicing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378035/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Close, Pierre -- East, Philip -- Dirac-Svejstrup, A Barbara -- Hartmann, Holger -- Heron, Mark -- Maslen, Sarah -- Chariot, Alain -- Soding, Johannes -- Skehel, Mark -- Svejstrup, Jesper Q -- A3560/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Mar 25;484(7394):386-9. doi: 10.1038/nature10925.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mechanisms of Transcription Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22446626" target="_blank"〉PubMed〈/a〉
Keywords:
Adaptor Proteins, Signal Transducing/genetics/metabolism
;
*Alternative Splicing
;
Animals
;
Carrier Proteins/genetics/metabolism
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Chromatin/genetics/metabolism
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Exons/genetics
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HEK293 Cells
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Heterogeneous-Nuclear Ribonucleoproteins/deficiency/metabolism
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Humans
;
Mice
;
Multiprotein Complexes/*chemistry/genetics/*metabolism
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RNA Interference
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RNA Polymerase II/*metabolism
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RNA, Messenger/*biosynthesis/*genetics/metabolism
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Ribonucleoproteins/chemistry/genetics/metabolism
;
*Transcription, Genetic
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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