Authors: Lauren Pulling, Future Science Group
Researchers from the Moffit Cancer Center (Tampa, FL, USA) have demonstrated a new method for controlling the activity of SETDB1, a protein involved in upregulating cancer cell growth. The team modulated SETDB1 activity via ubiquitination, and suggest that ubiquitination enzymes could be targeted in the development of novel cancer therapeutics.
Proteins can be modulated by ubiquitination, whereby a ubiquitin molecule is added to the protein. This modification can have a number of effects on protein activity: monoubiquitination can lead to activation of protein signaling pathways or target other proteins for modification, whereas the addition of many ubiquitin molecules can target a protein for degradation. Ubiquitination is usually carried out in three stages: activation by an E1 enzyme, conjugation by an E2 enzyme and ligation by an E3 enzyme.
In the new study, published in Molecular Cell, the team modulated activity of SETDB1, a protein that regulates DNA compaction and gene expression. When SETDB1 is active, target gene expression levels are repressed. The team performed molecular studies, demonstrating that SETDB1 is constitutively modified by monoubiquitination. This process is mediated by E1 and E2 enzymes; not E3 enzymes. Significantly, monoubiquitination is a constitutive component of SETDB1 function, halting its activity and leading to inhibition of target gene expression.
Research leader Jia Fang, (Moffit Cancer Center) commented: “This is the first demonstration that a constitutive monoubiquitination by an E2 enzyme complements the function of a key enzyme. These results suggest that this class of E2 enzymes is an attractive target for cancer therapeutics.”
Sources: Sun L, Fang J. E3-independent constitutive monoubiquitination complements histone methyltransferase activity of SETDB1. Mol. Cell doi:10.1016/j.molcel.2016.04.022 (2016) (Epub ahead of print); www.moffitt.org/newsroom/press-release-archive/2016/moffitt-researchers-find-new-way-to-control-genes-often-involved-in-cancer-growth/