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

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
elongation1–3. 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 1 T)-rich DNA, and is present at the affected exons. RNAinterference-
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.