Eukaryotes have a highly conserved enzymatic system for the ligation of ubiquitin (Ub) to proteins. Moreover, polypeptides distinct from but related to Ub, called Ub-like proteins or Ubls, can also be attached to proteins. Ligation to each Ubl has unique mechanistic and functional consequences. SUMO (small Ub-related modifier) is a highly divergent Ubl, and the SUMO ligation system has crucial roles in many organisms, including important contributions to human biology. Both Ub and SUMO attachment to proteins can be rapidly reversed in vivo, and specialized proteases are responsible for these cleavage reactions. The PI has been analyzing the deubiquitinating enzyme (DUB) family, primarily in the yeast Saccharomyces cerevisiae, and the first SUMO-specific proteases, the ULPs, were discovered in the PI's laboratory. ULP- class proteases are essential for embryogenesis in the mouse and are overexpressed in several human cancers. Therefore these enzymes have emerged as attractive targets for drug development. The long-range objective of the project is to gain a molecular understanding of the physiological and mechanistic roles played by DUBs and ULPs in vivo. In this renewal application, the proposed experiments are concentrated on SUMO modification in yeast and on the contributions of the two yeast desumoylating enzymes, Ulp1 and Ulp2, to SUMO system function. Mutation of either ULP has strong effects on growth and division, and Ulp1, like SUMO itself, is essential for cell-cycle progression. In broad terms, the goals are two-fold: Determine the molecular basis for key regulatory functions of the Ulp1 and Ulp2 enzymes and elucidate the molecular features of these SUMO proteases that are responsible for their dramatic differences in specificity and activity. Recent data on Ulp1 and Ulp2 have directed the studies into several specific areas of biological regulation. Based on these new findings, the following Aims are proposed: (1) Examine the function of Ulp1 at the nuclear pore complex, particularly its role in pre-mRNA nuclear retention;(2) Determine novel regulatory features of Ulp2, especially its role in chromatin regulation, and determine the contributions of Ulp2 noncatalytic domains to its in vivo regulation;and (3) Examine how SUMO attachment to substrates apparently promotes their ubiquitination by the heterodimeric Hex3-Slx8 Ub ligase.

Public Health Relevance

The growth and behavior of human cells, like those of virtually all complex organisms, is controlled by rapid attachment and removal of small specialized proteins (called ubiquitin-like proteins) to and from other proteins. Defects in the enzymes that control these processes are known to cause human developmental abnormalities, neurodegenerative disorders, and many different forms of cancer. This project aims to deepen our understanding of the enzymes that detach certain ubiquitin-like proteins from their partners, with the long-term goal of developing therapies to treat patients suffering from cancer and other diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Membrane Biology and Protein Processing (MBPP)
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Gerratana, Barbara
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Yale University
Schools of Medicine
New Haven
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Ryu, Hong-Yeoul; Hochstrasser, Mark (2017) Adaptive aneuploidy counters a dysregulated SUMO system. Cell Cycle 16:383-385
Beckmann, John F; Ronau, Judith A; Hochstrasser, Mark (2017) A Wolbachia deubiquitylating enzyme induces cytoplasmic incompatibility. Nat Microbiol 2:17007
Wilson, Nicole R; Hochstrasser, Mark (2016) The Regulation of Chromatin by Dynamic SUMO Modifications. Methods Mol Biol 1475:23-38
Ronau, Judith A; Beckmann, John F; Hochstrasser, Mark (2016) Substrate specificity of the ubiquitin and Ubl proteases. Cell Res 26:441-56
Gillies, Jennifer; Hickey, Christopher M; Su, Dan et al. (2016) SUMO Pathway Modulation of Regulatory Protein Binding at the Ribosomal DNA Locus in Saccharomyces cerevisiae. Genetics 202:1377-94
Ryu, Hong-Yeoul; Wilson, Nicole R; Mehta, Sameet et al. (2016) Loss of the SUMO protease Ulp2 triggers a specific multichromosome aneuploidy. Genes Dev 30:1881-94
Berk, Jason M; Hochstrasser, Mark (2016) Protein Modification: Bacterial Effectors Rewrite the Rules of Ubiquitylation. Curr Biol 26:R539-42
Hu, Ronggui; Hochstrasser, Mark (2016) Recent progress in ubiquitin and ubiquitin-like protein (Ubl) signaling. Cell Res 26:389-90
Hickey, Christopher M; Hochstrasser, Mark (2015) STUbL-mediated degradation of the transcription factor MAT?2 requires degradation elements that coincide with corepressor binding sites. Mol Biol Cell 26:3401-12
Kang, Hyeran; Bradley, Michael J; Cao, Wenxiang et al. (2014) Site-specific cation release drives actin filament severing by vertebrate cofilin. Proc Natl Acad Sci U S A 111:17821-6

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