The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer

Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically. [Display omitted] •Loss of the INTS6 subunit of Integrator confers resistance to CDK9 inhibition•INTS6 recruits PP2A to chromatin and forms a submodule of Integrator (Int-PP2A)•Int-PP2A opposes CDK9 at the phosphorylation level to fine-tune transcription•PP2A activators synergize therapeutically with CDK9 inhibitors in cancer Interplay between PP2A and CDK9 provides a control point for gene expression that can be exploited to inhibit tumorigenesis.