Department of Biomedical Research, National Jewish Health, Denver, United States; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States
Haolin Liu
Department of Biomedical Research, National Jewish Health, Denver, United States; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States
Ryan Hill
Department of Genetics and Biochemistry, School of Medicine, University of Colorado, Aurora, United States
Chunjing Chen
State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
Xia Hong
Department of Biomedical Research, National Jewish Health, Denver, United States; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States
Fran Crawford
Department of Biomedical Research, National Jewish Health, Denver, United States
Department of Pediatrics, Children Hospital, University of Colorado, Aurora, United States; Department of Pediatrics and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, United States
Qianqian Zhang
State Key Laboratory of Agrobiotechnology, China Agriculture University, Beijing, China
Xinjian Liu
Department of Dermatology, Duke University, Durham, United States
Zhongzhou Chen
State Key Laboratory of Agrobiotechnology, China Agriculture University, Beijing, China
Department of Pediatrics and the Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, United States; Department of Molecular and Cell Biology, University of California, Berkeley, United States
Department of Biomedical Research, National Jewish Health, Denver, United States; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States
John Kappler
Department of Biomedical Research, National Jewish Health, Denver, United States; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States
Department of Biomedical Research, National Jewish Health, Denver, United States; Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States
More than 30% of genes in higher eukaryotes are regulated by promoter-proximal pausing of RNA polymerase II (Pol II). Phosphorylation of Pol II CTD by positive transcription elongation factor b (P-TEFb) is a necessary precursor event that enables productive transcription elongation. The exact mechanism on how the sequestered P-TEFb is released from the 7SK snRNP complex and recruited to Pol II CTD remains unknown. In this report, we utilize mouse and human models to reveal methylphosphate capping enzyme (MePCE), a core component of the 7SK snRNP complex, as the cognate substrate for Jumonji domain-containing 6 (JMJD6)’s novel proteolytic function. Our evidences consist of a crystal structure of JMJD6 bound to methyl-arginine, enzymatic assays of JMJD6 cleaving MePCE in vivo and in vitro, binding assays, and downstream effects of Jmjd6 knockout and overexpression on Pol II CTD phosphorylation. We propose that JMJD6 assists bromodomain containing 4 (BRD4) to recruit P-TEFb to Pol II CTD by disrupting the 7SK snRNP complex.
