CDK12 and Integrator-PP2A complex modulates LEO1 phosphorylation for processive transcription elongation

• DOI: 10.1126/sciadv.adf8698
• Publication Date: 2023-05-19T17:58:22Z
• Authors: Min Qiu; Zhinang Yin; Honghong Wang; Lingyu Lei; Conghui Li; Yali Cui; Rong Dai; Peiyuan Yang; Ying Xiang; Qiuzi Li; Junhui Lv; Zhuang Hu; Min Chen; Hai-Bing Zhou; Pingping Fang; Ruijing Xiao; Kaiwei Liang
• Keywords: RNA polymerase II; Transcription

Cyclin-dependent kinase 12 (CDK12) interacts with cyclin K to form a functional nuclear that promotes processive transcription elongation through phosphorylation of the C-terminal domain RNA polymerase II (Pol II). To gain comprehensive understanding CDK12's cellular function, we used chemical genetic and phosphoproteomic screening identify landscape human CDK12 substrates, including regulators transcription, chromatin organization, splicing. We further validated LEO1, subunit polymerase-associated factor 1 complex (PAF1C), as bona fide substrate CDK12. Acute depletion or substituting LEO1 sites alanine, attenuated PAF1C association elongating Pol impaired elongation. Moreover, discovered is dephosphorylated by Integrator-PP2A (INTAC) INTAC II. Together, this study reveals an uncharacterized role for in regulating phosphorylation, providing important insights into gene its regulation.