During a cell division cycle, the genetic materials are organized, duplicated, and separated in the form of chromosomes. Our lab is interested in the molecular circuitries that ensure a timely and equal separation of chromosomes into the forming daughter cells. These circuitries choreograph a series of elegant chromosomal movements including cohesion, condensation, congression, separation, and segregation. Although the observations of these movements can be dated back in the mid 19th century when mitosis was first described, the mechanisms that temporally and spatially coordinate these dynamics are being elucidated only in the recent years. Knowing how cells divide their chromosomes is not only of fundamental cell biological interest itself, but also of great implications in tumorigenesis, a process closely correlated with massive aneuploidy and genetic instability.
Our lab is interested in the vertebrate mechanisms of chromatid cohesion and separation, the two processes that are crucial for chromatid partitioning. Cohesion refers to the protein linkage between sister DNA strands established immediately after DNA duplication. This process requires the four-subunit cohesin complex. Cohesion functions as a simple and effective sorting mechanism that enables a cell to know which two DNA strands are sisters. In higher eukaryotes, loss of cohesin occurs in two steps. In prophase cohesion between chromosome arms is lost and the linkage between sisters persists only at a specialized structure known as kinetochore. Final separation occurs at anaphase triggered by the endopeptidase separase. Separase dissolves cohesion by catalyzing two specific proteolytic cleavages on cohesin subunit MCD1/SCC1. This unleashes a simultaneous movement of all the chromosomes away from each other to the opposite poles of the mitotic spindle. One aim of our research is to identify all the molecular components that involve in these processes.
Proper temporal control of separase activity is critical for equal chromosome partition. In vertebrates, cohesin localize to chromosome at all stages of the cell cycle except anaphase. To prevent cohesin cleavage, either the activity of separase has to be inhibited or the cohesins have to be protected from exposing to separase. Separase is inhibited by two known mechanisms: affinity binding to inhibitor securin and inhibitory phosphorylation. Given the importance of timely separation of chromatids, the existence of multiple regulations is fully expected. Using a combination of molecular biology, biochemistry and cell biology approach, we are investigating the nature of the cellular signals that each inhibitory pathway responses to and exploring additional regulations that control separase action. In addition, we are trying to uncover other separase controlled cell cycle events by searching for additional substrates.
RECENT PUBLICATIONS
Stemmann, O.*, Zou, H.*, Gerber, S.A., Gygi, S.P., and Kirschner, M.W., "Dual inhibition of sister chromatid separation at metaphase" Cell, 107:715-726, 2001
Fajian Hou, and Hui Zou, "Two Human Orthologues of Eco1/Ctf7 Acetyltransferases Are Both Required for Proper Sister-Chromatid Cohesion" Molecular Biology of the Cell, 8/16:3908-3918, August 2005
Heng-Yu Fan, Qing-Yuan Sun, and Hui Zou, "Separase is Activated at the Metaphase I-II Transition in Xenopus Oocytes" Cell cycle, 5:in press, February 2006
Sun, Y., Yu, H., and Zou, H, "Nuclear Exclusion of Separase Prevents Cohesin Cleavage in Interphase cells" Cell Cycle, 5:2537-2542, 2006
Hou, F., Chu, C.W., Kong, X., Yokomori, K., Zou, H, "The acetyltransferase activity of San stabilizes the mitotic cohesin at the centromeres in a shugoshin-independent manner" J Cell Biology, 177:587-597, 2007
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