Human PC4 is a substrate-specific inhibitor of RNA polymerase II phosphorylation

The activity of cyclin-dependent protein kinases (cdks) is physiologically regulated by phosphorylation, association with the specific cyclin subunits , and repression by specific cdh. inhibitors. All three physiological regul atory mechanisms are specific for one or more cdks, but none is known to be substrate specific. In contrast, synthetic cdk peptide inhibitors that spe cifically inhibit cdk phosphorylation of only some substrates, "aptamers," have been described, Here, we show that PC4, a naturally occurring transcri ptional coactivator, competitively inhibits cdk-1, -2, and -7-mediated phos phorylation of the largest subunit of RNA polymerase I (RNAPII), but it doe s not inhibit phosphorylation of other substrates of the same kinases, Inte restingly, the phosphorylated form of PC4 is devoid of kinase inhibitory ac tivity. We also show that wild-type PC4 but not the kinase inhibitory-defic ient mutant of PC4 represses transcription in vivo. Our results point to a novel role for PC4 as a specific inhibitor of RNAPII phosphorylation.