New insight into chromosome segregation: Centromere-independent kinetochore assembly

One of the most critical tasks that a dividing cell must accomplish is the successful delivery of a complete set of genetic information to each new daughter cell. Now, a study published by Cell Press in the April 29th issue of the journal Cell, provides fascinating new insight into the complex of proteins that orchestrates the proper segregation of human chromosomes during cell division.

During the process of mitosis, DNA and its associated packing proteins are arranged into structures called chromosomes that are duplicated and then segregated. Duplicated chromosomes are attached together at a region called the centromere. The centromere plays an important role in the localization and assembly of a structure called the “kinetochore”. The kinetochore is composed of more than one hundred proteins and serves as the binding site for microtubules that are attached to opposite ends of the cell and will physically pull the two identical chromosomes apart. Without a centromere and a kinetochore, a chromosome would be lost during cell division.

Studying centromere DNA has proven a huge challenge as these sequences are neither necessary nor sufficient for kinetochore assembly. “Previous research identified a centromere protein called CENP-A as the key upstream factor required for specifying the site of kinetochore assembly,” explains senior study author Dr. Iain Cheeseman from the Whitehead Institute and Massachusetts Institute of Technology. “However, CENP-A is not sufficient for kinetochore formation in human cells. Our goal was to be able to define a mechanism that could direct the formation of a kinetochore at any site in the genome with high efficiency.”

In order to gain further insight into the mechanisms that act to direct the assembly of the remaining kinetochore proteins, the Cheeseman lab and their collaborators in the Fukagawa lab at the National Institute of Genetics in Japan analyzed CENP-C and the CENP-T/W complex, DNA-binding proteins that are present at the centromere of vertebrate cells and are required for formation of the kinetochore. Using an assay that essentially bypasses the centromere and targets the kinetochore to another area, the researchers assessed the requirement of proteins in kinetochore assembly. They found that in human cells, CENP-C and CENP-T/W could direct functional kinetochore formation in the absence of CENP-A.

“We found that although CENP-A is essential for specifying the site of kinetochore formation, CENP-T and CENP-C can act as key components to drive assembly of a functional kinetochore capable of binding microtubules to allow accurate chromosome segregation,” concludes first author Dr. Karen Gascoigne. “This suggests the possibility that such a system could be used to generate human artificial chromosomes. Previous attempts have been hampered by difficulties generating a functional centromeric region, a requirement that our method bypasses.”

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