Small ubiquitin related modifiers (SUMOs) function as posttranslational protein modifications and thereby regulate nearly all essential cell functions. As such, sumoylation is linked to a variety of human diseases, including cancer and neurodegenerative disorders, and there is great interest in targeting the SUMO pathway for therapeutic purposes. Notably, the first phase I clinical trial of a SUMO inhibitor was recently approved for cancer therapy. A more detailed understanding of basic molecular mechanisms regulating sumoylation and its consequences on cell function, however, is needed to achieve the full potential of these efforts. In particular, an ability to target specific branches of the SUMO pathway could allow for more precise therapies. Vertebrates express multiple SUMO paralogs which could allow for such precision targeting. However, the unique properties and functions of SUMO paralogs remain poorly understood. To address this gap in knowledge, we are taking advantage of recently developed SUMO1 and SUMO2 knockout cell lines to define and characterize the specific functions and molecular mechanisms of action of these two paralogs.
Aims of our proposal include: (1) We will obtain support for the hypothesis that SUMO1 and SUMO2 function as unique signals specifying unique fates upon conjugation to proteins. This will be achieved through detailed characterization of paralog-specific phenotypes identified in SUMO1 and SUMO2 knockout cell lines, including changes in cell morphology, defects in proteostasis and hypersensitivities to cell stress. (2) We will test multiple hypotheses to reveal the molecular basis for non-redundant functions of SUMO1 and SUMO2. Hypotheses concerning the function of chain formation and selective non-covalent interactions with effector proteins will be explored through rescue of knockout cell phenotypes using a panel of SUMO1 and SUMO2 mutant proteins. (3) We will use proteomic and transcriptomic studies to connect the non-redundant functions of SUMO1 and SUMO2 to paralog-specific changes in gene expression, target protein modification and association with interacting effector proteins. Results from our studies will provide unequivocal evidence for SUMO1 an SUMO2 paralog- specific functions and vital insights required to target specific branches of the SUMO pathway for therapeutic purposes.
Small ubiquitin related modifiers (SUMOs) function as posttranslational protein modifications and thereby regulate nearly all essential cell functions. As such, sumoylation is linked to a variety of human diseases, including cancer and neurodegenerative disorders, and there is great potential for targeting the SUMO pathway for therapeutic purposes. Our proposed studies will provide functional and mechanistic insights into differences between SUMO1 and SUMO2 paralogs expressed in human cells that will reveal unique contributions to health and disease and make it possible to target distinct branches of the SUMO pathway for more precise therapies.
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