Role of JMJD5 and JMJD6 in transcriptional pause release, The

Abstract

30-60% of genes in higher eukaryotes are regulated by promoter-proximal pausing of Pol II, thus representing a major transcription regulatory mechanism. Previously, we reported that two orphan Jumonji C domain (JmjC)-containing proteins, JMJD5 and JMJD7, have divalent cation-dependent protease activities that preferentially cleave histone tails containing methylated arginines. After the initial specific cleavage, JMJD5 and JMJD7, acting as aminopeptidases, progressively digest the C-terminal products to generate “tailless nucleosomes”, which could release the promoter-proximally paused RNA polymerase II (Pol II) into productive transcription elongation. We reveal structural and biochemical studies on JMJD5 and JMJD7 to understand the basis of substrate recognition and catalysis mechanism by this JmjC subfamily. Moreover, phosphorylation of Ser2 on Pol II-CTD by positive transcription elongation factor (P-TEFb) is a well-established necessary precursor event that enables productive transcription elongation. We reveal methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex which sequesters P-TEFb, as the cognate substrate for JMJD6’s novel proteolytic function. We propose that JMJD6 assists BRD4 to recruit P-TEFb to the CTD of Pol II by disrupting the 7SK snRNP complex.