Cyclin dependent kinases CDK8/19 are required for PKA inactivation during meiosis resumption

CDK8/19 are transcriptional cyclin dependent kinases, which do not directly control cell cycle progression. CDK8/19 are involved in regulation of multiple processes in embryogenesis, cancer progression, immune activation and others. Previously we demonstrated that CDK8/19 are critical for spermatogenesis in mice. Here we report that CDK8/19 activity is also required for oocyte maturation playing a significant role in meiosis resumption in mouse oocytes. Two chemically distinct CDK8/19 inhibitors - Senexin B and Snx631 prevented nuclear envelope breakdown and first polar body extrusion, blocking key molecular events required for exiting the dictyate - inhibition of PKA activity and activation of the CDK1/Cyclin B complex. This effect did not cause cytotoxicity, and oocytes could resume progression upon transfer into fresh media. Inhibition of CDK8/19 also prevented meiotic-specific mitochondrial expansion and clustering. Notably, these effects appear to be independent of roles of CDK8/19 in transcription, which is not required for resumption of meiosis. These findings for the first time demonstrate the roles of CDK8/19 activity in oocyte maturation, through its role in transcription-independent regulation of PKA activity.