Uhn-Soo Cho, Ph.D.

Kinetochore and centromere biology        

The kinetochore is a large macromolecular assembly that physically connects the centromere to spindle microtubules to ensure accurate distribution of sister chromatids to daughter cells during mitosis. Malfunction of the kinetochore results in genome instability, which has been implicated in many types of cancers. Cancer cells tolerate a small degree of genome instability, but cannot withstand high genomic instability. Therefore, perturbation of kinetochore assembly has long been an approach for preventing cancer cell proliferation. We have a long-standing interest in establishing the structural-functional relationship between kinetochore components. With a complete picture of the intact kinetochore, we will formulate a foundation for new cancer drug discoveries. We focus on fission yeast as a model organism due to its ease of genetic manipulation and protein crystallization with a conservation of key human kinetochore components. We have in vitro reconstituted key kinetochore components using novel multi-gene expression systems for both E. coli and insect cells.

Histone Chaperone and Karyopherins

Histone chaperones (HCs), such as Asf1, Rtt106, CAF-1, HIRA, and FACT, play important roles in nucleosome assembly during DNA replication and DNA repair. Understanding nucleosome assembly mechanisms by its chaperones is a crucial not only to understand how newly synthesized histones are recruited during DNA replication and repair, but also important to reveal transferring mechanism of epigenetic information to newly incorporated nucleosomes. As a long-term goal, we like to pursue the structural and biochemical studies of HCs and address questions of: What are structural features of those HCs as it is and as a complex with its substrates, histones? How HCs recognize and stabilize histones in solution? How HCs distinguish histone variants, e.g. histone H3.1 by CAF-1 and histone H3.3 by HIRA? What is the effect of H3 acetylation in transferring histones from Asf1 to either Rtt105 or CAF-1 and eventually nucleosome incorporation?

Sestrin2 and mTORC1

Constant exposure to a high nutrient diet and increased insulin levels often leads to type II diabetes and non-alcoholic fatty liver diseases. The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in this regulation and therefore has long been considered as an attractive target for type II diabetes. In this proposed research, we particularly focus on understanding the nutrient- and stress-dependent mTORC1 regulation pathway mediated by Sestrins, a stress-inducible protein family, using multi-directional approaches including x-ray crystallography, single particle cryo-electron microscopy and cell biology. Structural and biological studies of Sestrin and signaling intermediates of mTORC1, GATOR1 and GATOR2, will not only reveal the fundamental mechanism of how nutrient and stress can modulate mTORC1, but also provide the molecular platform to develop knowledge-based anti-diabetic medicines by targeting this pathway.