Centromere structure and function in neoplasia.

Abstract

The mammalian centromere plays an essential role in maintenance of diploidy in the cell. It is therefore imperative that we understand the structure and function of the mammalian centromere in order to plan strategy to control the incidence of aneuploidy and resultant malformations of the nonneoplastic as well as neoplastic tissues. Even though considerable information is available about the structure and some functional aspects of centromeres of lower eukaryotes such as yeast, the structure of the mammalian centromere is still a matter of conjecture limited to an understanding of the base composition of the alphoid sequences putatively located in the centromeric DNA of higher apes. We do, however, have a better understanding of the structure and role of the kinetochore. In all eukaryotes analyzed so far, the centromeres in a given genome separate in a sequential manner dependent upon the time of replication of pericentric and centromeric DNA. Some chromosomes, generally found in neoplastic cells, that carry more than one centromere show premature separation of the accessory centromeres. These centromeres and the associated pericentric regions replicate their DNA in an earlier part of the S phase than those that show kinetochore activity; both, however, carry DNA of the same composition. The active centromeres in these chromosomes show kinetochore protein binding as detected by antikinetochore antibody; the inactive centromeres are usually devoid of these proteins. The double minutes in neoplastic cells also lack kinetochore proteins, perhaps due to a lack of any centromere. Some dicentric and multicentric chromosomes in cancer cells and transformed cell lines do not display premature centromere separation. In these chromosomes, all centromeric sites show kinetochore proteins and all centromeric regions replicate their DNA simultaneously. These chromosomes also exhibited meiotic-like behavior of some centromeres and show postanaphase separation of some centromeres, resulting in bridges. These bridges, upon breakage and rejoining of sister chromatids, generate new multicentric chromosomes. The resulting chromosomes also exhibit formation of compound kinetochores. Some of these phenomena are novel descriptions of the centromere behavior in cancer cells. This review also discusses the role of aberrant centromere separation in human biology, providing correlates between errors of centromere separation and neoplasia.