CDK12/13 inhibition disrupts nucleolar morphology and promotes aberrant expression of IGS transcripts

Abstract

The transcription-associated cyclin dependent kinases (CDKs) 12 and 13 play important roles in the expression of RNAs involved in DNA damage repair and ribosomal proteins, yet their roles if any, in the regulation of ribosomal DNA expression are unclear. Here we show that these CDKs play critical roles in the processing and degradation of noncoding RNAs in the nucleolus and that inhibition of their function leads to the upregulation of unprocessed ribosomal RNA (rRNA) transcripts in the intergenic spacer (IGS) regions between ribosomal subunits. These upregulated RNAs are aberrantly polyadenylated by the TRAMP complex polymerase TENT4, and are represented as polyadenylated rings surrounding the nucleolus. The accumulation of these noncoding RNAs is associated with increased RNA polymerase II (Pol II)-mediated transcription coupled with failure of degradation by the MTREX (SKIV2L2) RNA helicase, a member of the RNA exosome complex whose expression is prematurely terminated by CDK12/13 inhibition. Altogether, these findings provide new insights into Pol II-mediated transcriptional regulation by CDK12/13 within the nucleolus.