title: DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation.
abstract: 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.
authors.affiliation: Mechanisms of Transcription Laboratory, Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms EN6 3LD, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Close
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.forename: A Barbara
authors.initials: AB
authors.lastname: Dirac-Svejstrup
authors.forename: Holger
authors.initials: H
authors.lastname: Hartmann
authors.forename: Mark
authors.initials: M
authors.lastname: Heron
authors.forename: Sarah
authors.initials: S
authors.lastname: Maslen
authors.forename: Alain
authors.initials: A
authors.lastname: Chariot
authors.forename: Johannes
authors.initials: J
authors.lastname: Söding
authors.forename: Mark
authors.initials: M
authors.lastname: Skehel
authors.forename: Jesper Q
authors.initials: JQ
authors.lastname: Svejstrup
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D005091:Exons / Q000235:genetics; D057809:HEK293 Cells; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000172:deficiency / Q000378:metabolism; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D002352:Carrier Proteins; D002843:Chromatin; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D046912:Multiprotein Complexes; D012333:RNA, Messenger; D012261:Ribonucleoproteins; C572345:ZNF326 protein, human; C026452:messenger ribonucleoprotein; D012319:RNA Polymerase II