For most of the billion or so times that cells divide in the average person, the process goes without a hitch. When cell division goes wrong, however, it can result in diseases that include cancer, fertility issues, and genetic disorders such as Down’s syndrome, in which cells have the wrong number of chromosomes.
During cell division, the replicated chromosomes are pulled apart so that one complete set ends up in each daughter cell. Researchers at Queen Mary University of London (QMUL) have now identified two small proteins that play a key role in ensuring that this chromosome transportation is carried out correctly. Viji Draviam, Ph.D., and colleagues hope their discoveries will provide new insights into molecular mechanisms that can cause aneuploidy, a condition in which cells have too many or too few chromosomes. The findings could also provide the foundation for future treatments for some cancers and rare aneuploidy-related diseases, and potentially even help to improve fertility treatment.
“Aggressive cancers often display irregular numbers of chromosomes,” Dr. Draviam stated. “Normal human cells usually have 23 pairs of chromosomes; however, cancer cells can have 50 or more chromosomes. To specifically diagnose the underlying reason for aneuploidy and also to specifically target or treat aneuploidy, one has to understand what causes aneuploidy in the first place.”
During cell division the chromosomes are divided between two daughter cells by the actions of rope-like structures called microtubules that comprise the mitotic spindle. The microtubules capture the chromosomes at a protein structure called the kinetochore and pull the two sets of DNA apart, explained Dr. Draviam, who is senior lecturer in structural cell and molecular biology from QMUL's School of Biological and Chemical Sciences.
“We have identified two proteins—tiny molecular machines—that enable the correct attachment between the chromosomes and microtubules. When these proteins don't function properly, the cells can lose or gain a chromosome. This finding gives us a glimpse of an important step in the process of cell division.”
Working with colleagues at the University of Cambridge, U.K., and the European Molecular Biology Laboratory in Heidelberg, Germany, the QMUL team used high-resolution microscopy to film human cells. They found that two proteins, Aurora-B kinase and BubR1-bound protein phosphatase 2 (PP2A), work in opposition to control the attachment of microtubules to chromosomes, through the addition or removal of phosphate groups.
The researchers published their work today in Nature Communications, in a paper entitled “Aurora-B Kinase Pathway Controls the Lateral to End-On Conversion of Kinetochore-Microtubule Attachments in Human Cells.”
“We found that a balance between Aurora-B kinase and BubR1-bound phosphatase is important to maintain correct chromosome numbers in human cells,” stated co-author Duccio Conti.
There are some rare genetic conditions that predispose people to aneuploidy. Patients with one such condition, mosaic variegated aneuploidy (MVA), are missing part of the BubR1 protein. This very rare condition can cause a wide range of developmental disorders, including microcephaly, restricted growth, brain and nervous system problems, and developmental delay, as well as seizures and increased cancer risk.
The QMUL researchers say they’d be interested to investigate whether reducing levels of Aurora B kinase protein in MVA patients might counteract the lack of BubR1. “Also we are curious to know whether chromosomes are captured normally in patients lacking BubR1-bound phosphatase,” Dr. Draviam noted. “This may reveal novel ways to tackle additional changes in chromosome numbers seen in patients who suffer from BubR1 mutations.”
Dr. Draviam further suggested that cellular levels of both Aurora B kinase and BubR1-bound phosphatase might also help inform fertility clinicians which healthy eggs to select for implantation, to increase the chances of a successful pregnancy. “By contributing to a molecular understanding of the chromosome segregation process, this work will support future development of predictive markers or drug targets for a variety of disorders linked to irregular chromosome numbers,” Dr. Draviam concluded.