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What we study?
POST-TRANSLATION ATTACHMENT OF SUMO REGULATES PROGRESSION THROUGH THE CELL CYCLE. SUMOylation is a reversibl e post-translational modification of proteins that regulates several cellular processes in eukaryotes. Several recent studies have implicated SUMOylation in regulating many crit ical functions in cell development. Components of the SUMOylation cascade have been demonstrated to regulate developmental processes such as formation of the synapto nemal  complex, maintenance of chromosome structure and segregation, cell cycle progression and DNA repair mechanisms.

Conjugation of SUMOp to substrate proteins occurs through a 3-step cascade that shares numerous similarities to the ubiquitin path  way. Precursor SUMOp undergoes cleavage by SUMO proteases to produce mature SUMOp. Mature SUMO is then activated by the heterodimeric activati n g enzyme (E1 enzyme Uba2/Aos1) in an ATP-dependent manner. The conjugating enzyme (E2 enzyme Ubc9p) works with several adapter protein (E3 ligases) to transfer SUMOp onto a Lys residue of the substrate protein. It controls diverse cellular mechanisms such as  localization and stability of substrate proteins and protein-protein interactions. W  hile many of the molecular mechanisms by which SUMOylation regulates its substrates remain elusive, modification by SUMOp generally alters protein-protein interactions. Attachment of SUMOp ca n also result in changes in the subcellular localization of substrate proteins. Lastly, SUMOylation can also compete with ubiquitylation and  lead to changes on protein stability.



Previous studies in the ciliate Paramecium tetraurelia in our lab demonstrated that SUMOp and its activating enzyme Ub a2p were upregulated during conjugat ion (sexual reproduction). RNAi treatment against either gene during se xual reproduction re sulted in the failure of macronuclear development suggesting that the SU MO pathway regulates progression through conjugation.

And why in Tetrahymena?
TETRAHYMENA OFFERS UNIQUE OPPORTUNITIES TO STUDY SUMOYLATION IN EUKARYOTES. The ciliate Tetrahymena thermophila separates its biological and genomic functions between two morphologically and functionally different nuclei. The polyploid macronucleus (MAC) is actively transcribed and responsible for gene expression that determines phenotype. The diploid micronucleus (mic) is transcriptionally silent and is responsible for germ-line functions. Conjugation in Tetrahymena is a complex and dynamic process that starts with meiosis, during which genetic exchange occurs, and terminates with MAC differentiation when a new MAC and mic are derived from the mitotic products of the zygotic nucleus in progeny cells. This process involves extensive programmed DNA rearrangements in the form of site-specific DNA deletions, de novo DNA methylation, histone acetylation and DNA amplification. Several proteins involved in these processes have been identified as SUMO substrates or as proteins that interact with components of the SUMO pathway. Examples of such substrates include DNA repair proteins Ku and XRCC4, septins Cdc3, Cdc10 and Cdc11 and the histone deacetylase HDAC1. Some have very well-defined roles in development, but the influence of SUMOylation on their activity in vivo has not yet been fully established and many substrates of SUMO are yet to be identified. We report that there is differential modification by SUMO between vegetative and mating Tetrahymena. SUMOylation increases as conjugation proceeds with the highest SUMO adduct formation observed during MAC differentiation suggesting that SUMOylation regulates numerous processes throughout conjugation.

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