Biologist Iain Cheeseman explores the complex structures that control cell division. Key to the process of cell division is the kinetochore, a cellular structure that holds onto each chromosome to guide it to the daughter cells during cell division. The kinetochore includes hundreds of proteins that interact with each other to maintain chromosomal stability. Cheeseman discovered many of these proteins, and has determined the functions of many more.
If there are uncorrected cell division errors, those errors can be catastrophic for the cell, with the potential to contribute to cancer progression. In fact, about 90 percent of cancer cells have the wrong number of chromosomes.
When cells prepare to divide, they build a kinetochore for each chromosome, linking the chromosome’s centromere — the junction where the two halves of a replicated chromosome are linked — to a spindle of protein microtubules that will pull each chromosome into one of the daughter cells. The kinetochore must interact very precisely with both the chromosome and the microtubules to ensure that each chromosome ends up in the right place.
Currently, many of the projects in Cheeseman’s lab relate to the architecture and organization of the kinetochore, including how it interacts with both chromosomes and microtubules. His lab uses a variety of experimental techniques to probe these questions.
In a study published in the journal Cell in July, a graduate student in Cheeseman’s lab, Kara McKinley, revealed new insights into how the kinetochore recognizes the correct chromosome location to bind to. In some species, such as yeast, this process depends on the DNA sequence at the centromere. However, that is not the case in human cells: Instead, the correct binding location is marked by a protein called CENP-A, which is found only at centromeres. This protein is recognized by a cascade of other proteins that recruit more CENP-A to the centromere when it is time for the cell to divide and form kinetochores. McKinley’s work defined the precise regulatory control that ensures this process occurs faithfully each time.
Cheeseman’s research could also lead to ways to create artificial human chromosomes with high efficiency, a goal that has so far eluded scientists. In 2011, Karen Gascoigne, then a postdoc in Cheeseman’s lab, discovered a kinetochore protein called CENP-T, which associates with other members of the Cenp family to form part of the kinetochore.
Wherever CENP-T is placed on a chromosome, it will recruit the proteins necessary to form the kinetochore, raising the possibility of creating artificial chromosomes that would replicate just like natural chromosomes inside living cells, which has been a huge challenge in human cells.
“This work told us a lot about the way the kinetochore is built, but it also provides a really valuable tool for being able to target kinetochore assembly and create artificial chromosomes,” Cheeseman says.
SOURCES – MIT News
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