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JMJD6 cleaves MePCE to release positive transcription elongation factor b (P-TEFb) in higher eukaryotes.

Authors
  • Lee, Schuyler1, 2
  • Liu, Haolin1, 2
  • Hill, Ryan3
  • Chen, Chunjing4
  • Hong, Xia1, 2
  • Crawford, Fran1
  • Kingsley, Molly5, 6
  • Zhang, Qianqian7
  • Liu, Xinjian8
  • Chen, Zhongzhou7
  • Lengeling, Andreas9
  • Bernt, Kathrin Maria6, 10
  • Marrack, Philippa1, 2
  • Kappler, John1, 2
  • Zhou, Qiang11
  • Li, Chuan-Yuan8
  • Xue, Yuhua4
  • Hansen, Kirk3
  • Zhang, Gongyi1, 2
  • 1 Department of Biomedical Research, National Jewish Health, Denver, United States. , (United States)
  • 2 Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, United States. , (United States)
  • 3 Department of Genetics and Biochemistry, School of Medicine, University of Colorado, Aurora, United States. , (United States)
  • 4 State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China. , (China)
  • 5 Department of Pediatrics, Children Hospital, University of Colorado, Aurora, United States. , (United States)
  • 6 Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, United States. , (United States)
  • 7 State Key Laboratory of Agrobiotechnology, China Agriculture University, Beijing, China. , (China)
  • 8 Department of Dermatology, Duke University, Durham, United States. , (United States)
  • 9 Max-Planck-Society, Administrative Headquarters, Munich, Germany. , (Germany)
  • 10 Department of Molecular and Cell Biology, University of California, Berkeley, United States. , (United States)
  • 11 Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States. , (United States)
Type
Published Article
Journal
eLife
Publisher
"eLife Sciences Organisation, Ltd."
Publication Date
Feb 12, 2020
Volume
9
Identifiers
DOI: 10.7554/eLife.53930
PMID: 32048991
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

In animals, an enzyme known as RNA polymerase II (Pol II for short) is a key element of the transcription process, whereby the genetic information contained in DNA is turned into messenger RNA molecules in the cells, which can then be translated to proteins. To perform this task, Pol II needs to be activated by a complex of proteins called P-TEFb; however, P-TEFb is usually found in an inactive form held by another group of proteins. Yet, it is unclear how P-TEFb is released and allowed to activate Pol II. Scientists have speculated that another protein called JMJD6 (Jumonji domain-containing 6) is important for P-TEFb to activate Pol II. Various roles for JMJD6 have been proposed, but its exact purpose remains unclear. Recently, two enzymes closely related to JMJD6 were found to be able to make precise cuts in other proteins; Lee, Liu et al. therefore wanted to test whether this is also true of JMJD6. Experiments using purified JMJD6 showed that it could make a cut in an enzyme called MePCE, which belongs to the group of proteins that hold P-TEFb in its inactive form. Lee, Liu et al. then tested the relationships between these proteins in living human and mouse cells. The levels of activated Pol II were lower in cells without JMJD6 and higher in those without MePCE. Together, the results suggest that JMJD6 cuts MePCE to release P-TEFb, which then activates Pol II. JMJD6 appears to know where to cut by following a specific pattern of elements in the structure of MePCE. When MePCE was mutated so that the pattern changed, JMJD6 was unable to cut it. These results suggest that JMJD6 and related enzymes belong to a new family of proteases, the molecular scissors that can cleave other proteins. The molecules that regulate transcription often are major drug targets, for example in the fight against cancer. Ultimately, understanding the role of JMJD6 might help to identify new avenues for cancer drug development.

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