|The long-term research interest of the Yu laboratory is to study 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 ( Fig. 1 ), 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 ( Fig. 2 ). 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.