Research

The small ubiquitin-like modifier (SUMO) protein, which is evolutionarily conserved and found in all eukaryotes, post-translationally modifies diverse substrates involved in various cellular processes, including transcription, DNA replication, cell cycle progression, nucleo-cytoplasmic transport, apoptosis, and genome stability. To uncover the biochemical activities and biological functions of SUMO modification, we have been working on SUMO function in epigenetics, cellular aging, and adaptive mechanism.

SUMO and epigenetics

The amino- and carboxy-terminal tails of histones are major targets for multiple post-translational modifications including acetylation, phosphorylation, methylation, and ubiquitylation. Additionally, all four core histones and the histone H2A variant H2A.Z are also all subject to SUMO modification in S. cerevisiae, whereas only sumoylated histones H3 and H4 have been identified in mammalian cells to date. However, it is yet unclear whether histone sumoylation generally contributes to transcription regulation. Therefore, we wish to understand, at a mechanistic and molecular level, what and how crosstalk between histone sumoylation and other histone modifications modulates various functions at chromatin level.

SUMO and cellular aging

The SUMO pathway has recently been implicated in the process of cellular senescence, the irreversible loss of cell replication potential that occurs during aging in vivo and in vitro. Preliminary results on comparative analysis of proteomics and mRNA levels between young and old human and murine tissues show elevated levels of global protein sumoylation and a decrease in components of the sumoylation process with age. Further connections between the SUMO pathway and the aging process remain to be elucidated. Lately, we found some candidates of SUMO substrates regulating cellular lifespan through in vitro evolution experiments allowing for the metabolic engineering of yeast strains by combining genetic variation with the selection of beneficial mutations in an unbiased fashion. Therefore, our current goals include identifying novel SUMO targets for improving the lifespan and elucidating the role of SUMO in cellular aging.

SUMO and adaptive mechanisms

SUMO is an essential regulator of cell homeostasis when cells encounter environmental stresses such as osmotic shock, hypoxia, heat, oxidative stress, nutrient deprivation, or genotoxic stresses, and protein sumoylation levels increase sharply in response to stress. Although the SUMO stress response is still not fully understood, it was previously reported that the Siz1 E3 ligase and Ulp2 SUMO protease are major factors involved in the SUMO stress response in S. cerevisiae. Recently, our group reported that distinct adaptive mechanisms counter a dysregulated SUMO system upon loss of the Ulp2 protease. To overcome the stress caused by the acute loss of Ulp2, mutant yeast cells become aneuploid which promotes compensatory mechanisms for rapid adaptation to Ulp2 loss. However, because aneuploidy is usually deleterious to cell fitness and such ulp2Δ cells exhibit severely impaired growth, long-term adaptation restores euploidy and leads to countervailing mutations in SUMO conjugation enzymes and regulatory shifts in ribosome biogenesis.

SUMO and diseases

The imbalance of sumoylation and desumoylation has been associated with the occurrence and progression of various diseases including cancer and Huntington’s, Alzheimer’s, and Parkinson’s diseases. In particular, we are currently focusing on the diseases related with the above three categories to establish the therapeutic strategies for the effective treatment of the diseases.