The centromere is a unique chromatin domain defined by the incorporation of a centromere specific nucleosome containing centromere protein-A (CENP-A). The centromere recruits the mitotic kinetochore to ensure the equal segregation of chromosomes during mitosis. The location of the centromere along the chromosome is determined by an epigenetic mechanism that relies on the CENP-A nucleosome. New CENP-A nucleosomes are assembled into the centromeres of dividing cells during a discreet time in early G1. Propagation of the centromere requires assembly of new CENP-A nucleosomes prior to DNA replication to avoid the loss of CENP-A nucleosomes through their successive dilution. Previously we determined Mis18 complex recruitment is the defining step in epigenetic inheritance. This proposal will explore the mechanism by which new CENP-A is recruited to centromeres through the recruitment of the Mis18 complex. Canonical histones are subject to multiple posttranslational modifications (PTMs) that drive the recruitment of chromatin associated factors and modify the function of the underlying chromatin. We will explore the function of two newly identified PTMs of the CENP-A tail, amino-terminal trimethylation and dual phosphorylation of serine 16 and 18. The experiments proposed here will significantly advance our understanding of the epigenetic mechanism of centromere inheritance. Furthermore, the impact of this work will extend beyond the centromere to provide significant insight into the propagation of epigenetic information encoded by acetylation and methylation or other histone variants.
Genomic instability is a major factor in the genesis and progression of cancer and can result from the missegregation of chromosomes during mitosis. Chromosome segregation is controlled by the centromere, a unique domain on the chromosomes, the core element of which is a unique nucleosome containing centromere protein-A (CENP- A). The experiments in this proposal will examine the earliest steps in establishing the centromere. They will identify a novel pathway for the stable inheritance of CENP-A nucleosomes with the potential to have important implications for the inheritance of a variety of epigenetic marks. In addition these experiments will identify the function of novel posttranslational modifications involved in the centromere function. The long-term goal is to understand how the perturbation of the centromere can lead to chromosome instability and cancer.
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