Chromosome replication and transmission are essential for the inheritance of genetic traits, but the mechanisms responsible for these processes remain poorly understood in multicellular eukaryotes. The centromere is required for kinetochore formation, which serves as the key attachment site to the spindle during mitosis and meiosis. Defects in centromere or kinetochore function result in aneuploidy, which is a hallmark of human cancers and is responsible for many birth defects. A pressing question in the centromere field today is how centromere identity is propagated from one generation to the next in multicellular eukaryotes. Our published and unpublished results demonstrate that the levels of centromeric chromatin proteins and their regulators are tightly regulated by gene expression and proteolytic mechanisms to ensure faithful centromere and chromosome propagation. This proposal integrates genetic, molecular, cell biological and biochemical approaches to identify the molecules and mechanisms that regulate the levels of centromeric chromatin proteins, and promote the assembly and propagation of centromeric chromatin, using Drosophila cell culture and animal tissues. The entry point into centromeric chromatin is a conserved histone H3-like protein (CENP-A, CID in flies) that localizes exclusively to functional centromeres. We previously identified key regulators of CENP-localization and assembly, as well as a link between cell cycle regulation and centromere formation, which provide an intellectual and technical foundation for the proposed aims. The specific focus of this proposal is to elucidate the cell cycle regulation of centromeric protein stability and the consequences of misregulation by investigating: 1) how mutual protection and other mechanisms regulate the stability of CID and its chaperone CAL1, 2) the impact of centromere protein misregulation on cells, tissues and the organism, and 3) how centromere protein misregulation contributes to cancer initiation and progression in Drosophila model of glioblastoma. The deeper understanding of the normal regulation of centromere assembly generated by these studies will provide basic information about this essential biological process, insights into mechanisms responsible for the etiology of aneuploidy associated with cancer and birth defects, and ultimately will lead to the development of tools for diagnosis and treatment of human diseases associated with centromere defects, such as cancer.
Human cancers uniformly contain massive numbers of chromosome rearrangements and other consequences of genome instability. Centromere dysfunction is one cause of genome instability, and misexpression of the centromeric histone and other factors involved in centromere assembly that we study has been observed in a wide spectrum of human cancers, including colon, glial, liver and breast tumors. The results of this project will provide key information about the normal regulation of centromere protein stability and function in Drosophila cells and animals, as well as a detailed understanding of the impact of centromere protein misregulation on genome stability, gene expression, and the initiation and progression of cancer in a Drosophila model for glioblastoma, which will ultimately contribute to the development of cancer diagnostic and treatment tools.
| Takada, Mamoru; Zhang, Weiguo; Suzuki, Aussie et al. (2017) FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A. Cancer Res 77:4881-4893 |
| Zhang, Weiguo; Mao, Jian-Hua; Zhu, Wei et al. (2016) Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy. Nat Commun 7:12619 |
