DBIRD Complex Integrates Alternative Mrna Splicing with RNA Polymerase II Transcript Elongation

Characterization of the human interactome of chromatin-associated messenger ribonucleoprotein particles identifies DBC1 and a new protein (ZIRD) as subunits of a protein complex (DBIRD) that binds directly to RNAPII, regulates alternative splicing of exons embedded in (A + T)-rich DNA, and whose depletion results in region-specific decreases in transcript elongation. Studies in recent years have shown how the processes involved in making, processing and splicing RNA are linked. Jesper Svejstrup and colleagues now describe a previously unknown protein complex called DBIRD, which links RNA transcript elongation to splicing. This complex binds the RNA polymerase and affects alternative splicing of a subgroup of messenger RNAs by promoting transcription across (A + T)-rich DNA encoding exons. 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 elongation1,2,3. 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 transcript4. 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.