The Stowers Institute's Conaway Lab has demonstrated that an enzyme called Uch37 is kept in check when it is part of a human chromatin remodeling complex, INO80. The results were published in today's issue of Molecular Cell.
Uch37 is a "deubiquitinating enzyme" that can remove protein tags (called ubiquitin) from other proteins. The presence of one kind of ubiquitin tag on a protein can mark it for destruction, but others serve as marks to affect the activity of a protein. INO80 is a chromatin remodeling complex that is believed to function in both gene regulation and DNA repair by "unpacking" DNA from nucleosomes to allow access to chromosomal DNA.
Previously, the Conaway Lab demonstrated that Uch37 is associated with another multiprotein complex, the proteasome — a large protein complex that degrades unneeded or damaged proteins. In the new paper, the team shows that when bound to INO80, Uch37 can also be activated in the presence of proteasomes. Although the mechanism involved isn't totally clear, it seems to occur via a "touch and go" mechanism, in which proteasomes interact transiently with Uch37.
"Our findings suggest that activation of INO80-associated Uch37 by transient association of proteasomes with the INO80 complex could be one way proteasomes help to regulate gene expression," said Tingting Yao, Ph.D., Postdoctoral Research Fellow and lead author on the paper.
"Tingting's discovery of communication between INO80 and the proteasome provides new clues into the functions of both of these regulatory complexes," said Joan Conaway, Ph.D., Investigator and senior author on the paper. "In addition, it provides new insights into how deubiquitinating enzymes can be regulated — the ability to regulate these enzymes is very important because promiscuous removal of ubiquitin marks could lead to a failure to regulate properly the activities or levels of key enzymes and proteins in cells."
The ultimate goal of the Conaway Lab is to understand how genes are turned on and off during transcription and how regulation of chromatin structure contributes to this process. Proper gene regulation is key for normal development and functioning of all organisms, including humans. Misregulation of gene expression can contribute to many diseases.
Additional contribution authors from the Stowers Institute include Jingji Jin, Ph.D., Senior Research Associate; Yong Cai, Ph.D., Research Specialist I; Hidehisa Takahashi, Ph.D., Postdoctoral Research Associate; Selene Swanson, Research Specialist II; Michael Washburn, Ph.D., Director of Proteomics; Laurence Florens, Ph.D., Managing Director of Proteomics; and Ron Conaway, Ph.D., Investigator. Contributing authors from other institutions include Ling Song, Ph.D., Carver College of Medicine, University of Iowa; and Robert Cohen, Ph.D., Bloomberg School of Public Health, Johns Hopkins University.
Drs. Joan and Ron Conaway hold faculty appointments in the Department of Biochemistry & Molecular Biology at The University of Kansas School of Medicine. Learn more about their work at www.stowers-institute.org/labs/ConawayLab.asp.
About the Stowers Institute
Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing, treating, and curing disease. The Institute was founded by Jim and Virginia Stowers, two cancer survivors who have created combined endowments of $2 billion in support of basic research of the highest quality.
Journal
Molecular Cell