The National Institute for Biotechnology
in the Negev Ltd.
Ben-Gurion University of the Negev

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Research Field

Lysine methylation has emerged as a prominent post-translational modification of protein with fundamental impact on the initiation and progression of many biological processes. The methylation of lysine residues is catalyzed by protein lysine methyltransferases (PKMTs). Today, there are over 60 candidate members of this enzyme family. The large number of enzymes devoted to placing methyl groups on lysine residues argues for the presence of numerous protein substrates beyond the few that have been characterized to date. As such, PKMT activity represents an attractive target for drug design, with compounds that manipulate the cellular activity of these enzymes holding enormous therapeutic potential.

Peptides are a promising tool for targeting proteins since they are easily synthesized, possess high target specificity and selectivity, and cause cytotoxicity at levels that are considered low. The use of peptides which include natural motifs that specifically influence methyltransferase activity and intracellular interactions with their partners may be a promising approach for selective inhibition of PKMTs. Indeed, therapeutic peptides are being used as a novel approach for treating numerous diseases, including cancer.

In recent years, the Levy laboratory has identified and characterized the enzymatic activity, substrate specificity, crystal structure, and cellular and physiological functions of the PKMT SETD6. They have shown that substrates of SETD6-mediated methylation are associated with oncogenic signaling pathways and that SETD6 may play a direct role in regulating these pathways. To manipulate SETD6 activity, Dr. Levy and his team have designed several peptides and shown biochemically that they specifically inhibit SETD6 enzymatic activity both in vitro and in cells. Cellular viability assays revealed that their designed peptides possess the ability to kill a significant portion of cancers derived from cervical, breast, and glioblastoma cancer cell lines and could significantly reduce tumor size in several mouse models.

Prof. Dan Levy

The major focus of Prof. Levy’s laboratory is to elucidate the biological roles of lysine methylation in modulating intracellular signaling pathways. In their research, the Levy team relies on interdisciplinary biochemical and cellular approaches, together with cutting-edge genomic and proteomic tools, to decipher the molecular mechanisms by which lysine methylation through epigenetics programs regulates oncogenic and cell differentiation processes. Prof. Levy and his colleagues seek to identify new events of methylation of histone and non-histone proteins, in order to define the molecular mechanisms by which these methyl marks are generated and transduced, and to unravel the biological functions of such methylation events. The long-term goal of the Levy group is to exploit this knowledge for the development of new cancer therapies.

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