Postdoctoral Fellow in the Black Lab, Perelman School of Medicine at the University of Pennsylvania
We are taking a quick break from our regular Alumni Spotlight format to spotlight newly published research from Dr. Nootan Pandey. An alumna of the Department of Molecular Biosciences, Dr. Pandey is currently a Postdoctoral Fellow in the Perelman School of Medicine at the University of Pennsylvania.
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Cells utilize a novel metaphase checkpoint to prevent chromosome mis-segregation.
Cells are the basic unit of life that comprises DNA to store the genetic details. Our genetic information is stored in a unique structure called chromosomes. A chromosome is a thread-like structure of DNA and proteins stockpiled in the nucleus of a cell. In humans, each cell has 23 pairs of chromosomes (a total of 46) inherited from each of your parents.
During development and growth, a parent cell divides into two daughter cells via cell division. Mitosis is a type of cell division that allows chromosome segregation to daughter cells. Faithful chromosome segregation is important to maintain the genomic integrity in cells. Chromosome mis-segregation promotes aneuploidy and can drive many diseases such as cancer. To avoid this catastrophic event cells possess an intracellular surveillance mechanism known as “metaphase checkpoint”. Despite cell biologists have made good progress in understanding the underlying mechanism involved in chromosome segregation the molecular insight into this checkpoint is lacking.
In a collaborative study, Dr. Yoshiaki Azuma’s group from the Department of Molecular Biosciences at the University of Kansas and Dr. Duncan Clarke’s group in the College of Biological Sciences at the University of Minnesota have provided the molecular insight into metaphase checkpoint regulation. KU and UMN researchers have utilized Xenopus egg extracts and human cells in their study. This study shows catalytic disruption of DNA Topoisomerase II α in a certain conformation leads to metaphase checkpoint activation. Topoisomerase II α is an essential enzyme during mitosis that plays a major role in the chromosome disjunction. Topoisomerase II α resolves tangled DNA threads between sister chromatids using its unique catalytic activity. Therefore, topoisomerase II α is also an important clinical target for many anti-microbial and anti-cancer drugs.
What does this mean?
Researchers have published a paper in Journal of cell biology and dissected the molecular events involved in metaphase checkpoint activation. This study has provided evidence that SUMOylation (a post-translational modification) of Topoisomerase II α acts as a signal transducer for metaphase checkpoint and causes Aurora B mislocalization on the chromosomes. Aurora B is an important kinase and is precisely recruited to the centromere region in metaphase. Aurora B recruitment at the centromere is crucial to allow chromosome segregation on time. Additionally, Dr. Clarke’s group was able to monitor mitotic delay in human cells upon metaphase checkpoint activation. This checkpoint activation provides additional time to cells to resolve tangled DNA. Notably, topoisomerase II α SUMOylation mediated Aurora B mislocalization is the main readout for this novel metaphase checkpoint. These findings revealed that a metaphase checkpoint is activated to prevent chromosome mis-segregation in cells when Topoisomerase II activity is inhibited. Lastly, researchers at KU and UMN believe that understanding the molecular mechanism of metaphase checkpoint will provide insights into the causes of chromosome mis-segregation and developing targeted cancer therapies.
This research was funded by National Institutes of Health grants R01GM112793 and R01GM130858; the University of Minnesota Foundation; the University of Minnesota Office of the Vice President for Research; and University of Kansas Strategic Initiative Grant (INS0073115).
2020 Pandey N. et. al, JCB: Topoisomerase II SUMOylation activates a metaphase checkpoint via Haspin and Aurora B kinases.
A HeLa cell chromosome showing Aurora B mislocalization when Topoisomerase IIa is chemically inhibited.
(A) Aurora B recruitment is defined at the inner centromere in the control chromosome.
(B) Chromosome treated with ICRF-193 (a catalytic inhibitor of Topoisomerase II) shows abnormal mislocalization of Aurora B. Aurora B Kinase (green) and CREST; an inner centromere marker protein (red). Image courtesy of Dr. Duncan Clarke.