Centromere Identity and Function

描述（由申请人提供）：细胞分裂时染色体相等分裂的缺陷会导致非整倍体，这是一种遗传灾难，如果在配子中出现，会导致自然流产或出生缺陷，这是几乎所有人类癌症中基因剂量失衡的主要原因。着丝粒是每条染色体上的位点，它在健康细胞的细胞分裂中指导染色体的精确分离。这个项目的重点是解决关于着丝粒的两个相关的主要问题：什么是人类着丝粒的表观遗传标记的本质，以及这种表观遗传标记是如何通过细胞分裂繁殖的？着丝粒是在细胞分裂时赋予遗传稳定性的染色体位点，但在这些位点上发现的典型DNA序列并不是必需的

DESCRIPTION (provided by applicant): Defects in the equal partitioning of chromosomes at cell division causes aneuploidy, a genetic catastrophe that results in spontaneous abortion or birth defects if it arises in the gametes and that is a major contributor to gene dosage imbalances in almost all human cancers. The centromere is the locus on each chromosome that directs accurate chromosome segregation at cell division in healthy cells. The focus of this project is to address two related major questions regarding centromeres: what is the nature of the epigenetic mark that specifies human centromeres and how is this epigenetic mark propagated through cell divisions? Centromeres are the chromosomal loci that confer genetic stability at cell division, but the DNA sequences typically found at the loci are neither necessary nor sufficient for centromere function. Rather, centromeres are specified in metazoans and many other eukaryotes through an epigenetic process. Key to epigenetic centromere specification is a histone H3 variant, CENP-A, and in this proposal we now build on the major findings we made in the previous funding cycle regarding its structure/dynamics, cell cycled-coupled chromatin assembly, and the organization and recruitment of centromere components it directs to human centromeres and neocentromeres. We have identified three critical areas of investigation that are now ripe for eliciting major insight at centromeres: 1) identifying the majo form of the histone/DNA particle into which it assembles at functional human centromeres-representing the fundamental unit of centromeric chromatin and the prime candidate to epigenetically specify centromere location, 2) determining the molecular basis for the cell cycle-coupled program of centromere inheritance, and 3) investigating the stability of CENP-A nucleosomes at individual centromeres and the role therein of other centromere constituents. We will pursue these topics using biochemical, genomic, proteomic, molecular genetic and cell biological approaches, and together these studies have the promise to generate valuable insight into the epigenetic mechanisms that specify and maintain centromere location on the chromosome.