Research

  • USP7 Inhibition

USP7 in cancer:

USP7 is a de-ubiquitinating enzyme responsible for maintenance of several oncoproteins and tumor suppressors in the cell via the ubiquitin-proteasomal pathway. It is an attractive potential drug target for cancer therapy due to its role as a major regulator of p53 pathway. We investigate molecular mechanisms of USP7 activation and substrate specificity to gain detailed understanding of the USP7 enzymatic function and provide structural basis for drug discovery.

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SUMO E3 ligase PML as a sensor of stress:

The promyelocytic leukemia protein (PML) is an E3 SUMO ligase involved in regulation of various critical processes in the cell, including DNA repair, senescence, apoptosis, antiviral responses, and the oxidative stress response. In response to oxidative stress and viral infections PML forms spherical compartments in the nucleus known as PML nuclear bodies (PML-NBs). Functionally, PML bodies may sequester, modify or degrade partner proteins. Our laboratory studies molecular mechanism of PML-NB formation in response to Herpes Simplex 1 (HSV1) infection. By characterizing structure, dynamics and oligomerization of PML protein we reveal PML features that make it a potent sensor of stress. This work may lead to development of new effective HSV1 treatments, and safer treatments for promyelocytic leukemia.

 

UBE3A in Angelman Syndrome:

Angelman Syndrome (AS) is a rare neurodevelopmental disorder caused by the loss UBE3A gene expression. In humans, UBE3A gene encodes three isoforms of the ubiquitin ligase E6AP. These isoforms differ only at their N-termini, with isoforms 2 and 3 having an additional 23 and 20 amino acid residues, respectively, that are not present in isoform 1. Data from the murine homolog, Ube3a, indicate differences in function and sub-cellular location among the three isoforms. However, the expression of all three protein isoforms in humans has only recently been demonstrated, and very little is currently known about human isoform-specific function and localization. We study structural and functional differences between the E6AP isoforms in humans.

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Zn-binding AZUL domain of human ubiquitin protein ligaseĀ Ube3A