My laboratory studies cellular mechanisms that govern chromosome inheritance and integrity using a combination of cell biological, biochemical, and biophysical methods. Genomic DNA is packaged into highly compacted chromatin. The nucleosome core particle is the basic building block of chromatin and consists of 147 base pairs of DNA and a histone octamer. Histone modifications regulate chromatin structure and dynamics, which in turn affect all processes that need to access genomic DNA, including DNA replication, sister-chromatid cohesion and segregation, and DNA repair.
During the cell cycle, cells duplicate their chromosomes in S phase, physically tether the replicated chromosomes through cohesin to establish sister-chromatid cohesion, and then partition the sister chromatids evenly into the two daughter cells in mitosis. Chromosome segregation is triggered by the removal of cohesin, which occurs in two steps in human cells. In prophase, polo-like kinase 1 (Plk1) phosphorylates and removes cohesin from chromosome arms, but spares a pool of cohesin at centromeres. At the metaphase?anaphase transition, the anaphase-promoting complex or cyclosome (APC/C) mediates the ubiquitination and degradation of securin, an inhibitor of separase. Cleavage of centromeric cohesin by separase then allows sister-chromatid separation. A cell cycle surveillance system called the spindle checkpoint prevents premature sister-chromatid separation in response to misaligned chromatids that are not properly captured by spindle microtubules.
Sister-chromatid cohesion is also required for the efficient repair of DNA double-strand breaks (DSBs) within the genome through homologous recombination (HR) between sister chromatids. Cohesin is loaded after S phase at DSBs (termed postreplicative cohesin loading) and facilitates HR by physically holding the two sister chromatids in close proximity.
Sister-chromatid cohesion, segregation, and recombination are interdependent processes and are temporally coordinated during the cell cycle. All three processes are regulated by the underlying chromatin structure either locally or globally. We aim to understand the interplay and coordination of these processes, which are of fundamental importance in cell biology. In addition, uneven distribution of sister chromatids in mitosis or inefficient repair of DSBs result in aneuploidy or chromosome translocations, which are two prevalent forms of genomic instability in cancer cells. Our studies will also provide a better molecular understanding of chromosome instability in human cancers.
RESEARCH INTERESTS
Cell cycle checkpoints
Chromosome segregation
Protein structure and folding
Histone modifications
DNA repair
RECENT PUBLICATIONS
Luo X., Tang Z., Xia G., Wassmann K., Matsumoto T., Rizo J., and Yu H., "The Mad2 spindle checkpoint protein has two distinct natively folded states." Nat. Struct. Mol. Biol., 11:338-345, 2004
Tang, Z., Shu, H., Oncel, D., Chen, S., and Yu, H., "Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint." Mol. Cell, 16:387-397, 2004
Tang, Z., Shu, H., Qi, W., Mahmood, N., Mumby, M. C., and Yu, H., "PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation." Dev. Cell, 10:575-585, 2006
Yang, M., Gocke, C. B., Luo, X., Borek, D., Tomchick, D. R., Machius, M., Otwinowski, Z., and Yu, H., "Structural basis for CoREST-dependent demethylation of nucleosomes by the human LSD1 histone demethylase" Mol. Cell, 23:377-387, 2006
Potts, P. R. and Yu, H., "The SMC5/6 complex maintains telomere length in ALT cancer cells through sumoylation of telomere-binding proteins" Nat. Struct. Mol. Biol., 14:581-590, 2007
SIGNIFICANT PUBLICATIONS
Yu, H., Chen, J. K., Feng, S., Dalgarno, D. C., Brauer, A. W. and Schreiber, S. L., "Structural basis for the binding of proline-rich peptides to SH3 domains." Cell, 76:933-945, 1994
Yu, H., Peters, J.P., King, R. W., Page, A., Hieter, P., and Kirschner, M. W., "Identification of a cullin homology region in a subunit of the Anaphase-Promoting Complex." Science, 279:1219-1222, 1998
Luo, X., Tang, Z., Rizo, J., and Yu, H., "The Mad2 spindle checkpoint protein undergoes similar major conformational changes upon binding to either Mad1 or Cdc20." Mol. Cell, 9:59-71, 2002
Tang, Z., Sun, Y., Harley, S. E., Zou, H., and Yu, H., "Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint." Mol. Cell, 16:387-397, 2004
Tang, Z., Shu, H., Qi, W., Mahmood, N., Mumby, M. C., and Yu, H., "PP2A is required for centromeric localization of Sgo1 and proper chromosome segregation" Dev. Cell, 10:575-585, 2006
Point and right click (click and hold for Mac users) your mouse onand select "Save this link (or target) as..." option to save the file to your local computer.
and select "Save this link (or target) as..." option to save the file to your local computer.