New module of transcriptional regulator Integrator links its cleavage subunit and RNA/DNA

Integrator is a huge RNA processing machinery of 14 subunits that is implicated in numerous diseases but the molecular basis of its functions remains unknown. In their recent paper the Jonas group showed that three subunits of Integrator, namely INTS10/13/14, form a stable subcomplex in human cells. This finding suggests that the large holo-complex consists actually of multiple smaller modules that need to assemble to carry out cleavage of target transcripts. The new module is important for the processing of short non-coding RNAs but it has a more vital role in the attenuation of mRNA transcription.

Structural investigation of the new subcomplex revealed a highly unusual interlinked protein complex with a surprising similar organization as a known DNA repair machinery. As suggested by this structural homology the module binds different types of nucleic acids such as DNA and RNA. Hairpin RNAs are bound with the highest affinity, which could explain why Integrator cleaves non-coding RNAs with a terminal hairpin with higher efficiency.

Furthermore, subunit INTS13 directly binds the cleavage module of Integrator via a conserved peptide motif. Thus, the study identified a direct link between nucleic acids and the cleavage subunit of Integrator. Disruption of this interaction impairs processing of non-coding RNAs and in the context of whole organisms inhibits spermatogenesis. Together the data suggests that the module works in Integrator mediated transcription regulation during cell differentiation as well as in RNA processing by bringing RNA targets and nuclease into proximity.
 

Link to the paper in external page "Nature Communications".