JMJD5 couples with CDK9 to release the paused RNA polymerase II
Haolin Liu, Srinivas Ramachandran, Nova Fong, Tzu Phang, Schuyler Lee, Pirooz Parsa, Xinjian Liu, Laura Harmacek, Thomas Danhorn, Tengyao Song, Sangphil Oh, Qianqian Zhang, Zhongzhou Chen, Qian Zhang, Ting-Hui Tu, Carrie Happoldt, Brian O’Conner, Ralf Janknecht, Chuan‐Yuan Li, Philippa Marrack, John W. Kappler, Sonia M. Leach, Gongyi Zhang
Abstract
More than 30% of genes in higher eukaryotes are regulated by RNA polymerase II (Pol II) promoter proximal pausing. Pausing is released by the positive transcription elongation factor complex (P-TEFb). However, the exact mechanism by which this occurs and whether phosphorylation of the carboxyl-terminal domain of Pol II is involved in the process remains unknown. We previously reported that JMJD5 could generate tailless nucleosomes at position +1 from transcription start sites (TSS), thus perhaps enable progression of Pol II. Here we find that knockout of JMJD5 leads to accumulation of nucleosomes at position +1. Absence of JMJD5 also results in loss of or lowered transcription of a large number of genes. Interestingly, we found that phosphorylation, by CDK9, of Ser2 within two neighboring heptad repeats in the carboxyl-terminal domain of Pol II, together with phosphorylation of Ser5 within the second repeat, HR-Ser2p (1, 2)-Ser5p (2) for short, allows Pol II to bind JMJD5 via engagement of the N-terminal domain of JMJD5. We suggest that these events bring JMJD5 near the nucleosome at position +1, thus allowing JMJD5 to clip histones on this nucleosome, a phenomenon that may contribute to release of Pol II pausing.