DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation

TY - JOUR

T1 - DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation

AU - Close, Pierre

AU - East, Philip

AU - Dirac-Svejstrup, A Barbara

AU - Hartmann, Holger

AU - Heron, Mark

AU - Maslen, Sarah

AU - Chariot, Alain

AU - Söding, Johannes

AU - Skehel, Mark

AU - Svejstrup, Jesper Q

PY - 2012/4/19

Y1 - 2012/4/19

N2 - 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.

AB - 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.

KW - Adaptor Proteins, Signal Transducing

KW - Alternative Splicing

KW - Animals

KW - Carrier Proteins

KW - Chromatin

KW - Exons

KW - HEK293 Cells

KW - Heterogeneous-Nuclear Ribonucleoproteins

KW - Humans

KW - Mice

KW - Multiprotein Complexes

KW - RNA Interference

KW - RNA Polymerase II

KW - RNA, Messenger

KW - Ribonucleoproteins

KW - Transcription, Genetic

U2 - 10.1038/nature10925

DO - 10.1038/nature10925

M3 - Journal article

C2 - 22446626

SN - 0028-0860

VL - 484

SP - 386

EP - 389

JO - Nature Study

JF - Nature Study

IS - 7394

ER -