Every time a human cell divides, it must pull its duplicated DNA apart into two identical sets—and when this process fails, the resulting errors can trigger cancer or cause birth defects. The problem is that the molecular machinery responsible for this separation, called the mitotic spindle, is built from thousands of tiny protein filaments inside the cell, and the attachment of chromosomes to those filaments must be near-perfect. A built-in quality-control system, the spindle assembly checkpoint, is supposed to catch mistakes, but it sometimes fails. Researchers at the University of Oxford want to understand exactly how the spindle forms, how chromosomes attach to it, and how the checkpoint works—by identifying the enzymes that add or remove chemical tags (phosphorylations and acetylations) that switch key proteins on or off during cell division. This is fundamental science. It will not produce a new drug or diagnostic tomorrow. But understanding the basic rules of chromosome segregation could eventually reveal new targets for cancer therapies that exploit the vulnerability of aneuploid cells, and may also shed light on the mechanisms behind certain inherited birth defects.
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When cells divide, the genetic material, DNA, has to be duplicated and then shared equally between the two daughter cells in the form of chromosomes. If anything goes wrong during this process, chromosomes may be lost or gained. If this happens, further cell divisions will be impaired, leading to cell death or initiating cancer development. Indeed, unequal segregation of the genetic material, a condition called aneuploidy, is considered a hallmark as well as a driving force of cancer. My research team at the Department of Biochemistry at the University of Oxford will analyse the regulatory mechanisms that ensure the reliability of chromosome segregation in mammalian cells. For this work we will use human tumor cells grown in tissue culture. When cells divide a molecular chromosome division machinery, the mitotic spindle, is build inside the cell out of minute building blocks called microtubules. These form strings that the chromosomes attach to. Once properly attached, the chromosomes are pulled into the daughter cells. Stable attachment of the chromosomes to the microtubules is critical, since faulty attachments may result in chromosomes getting lost. There is a cellular control machinery termed the "spindle assembly checkpoint" that checks that all the chromosomes are properly attached to microtubules before the chromosomes are divided but sometimes this safeguard fails. We are interested in understanding the different aspects that contribute to the faithfulness of chromosome segregation. How is the formation of the mitotic spindle regulated? How do the chromosomes attach to the microtubules? How is this controlled? How does the spindle assembly checkpoint function? We will identify molecules that contribute to both the attachment process and the control mechanisms and analyse how these are regulated. One common form of regulation in cells is the attachment of distinct small chemical tags to molecules that do specific jobs. We are particularly interested in tags called "phosphorylations" and "acetylations". These tags alter the function of the molecule they have been attached to, e.g. switch it on or off or change its interaction with other proteins. We believe that the cellular machines, the enzymes, that add, remove and control the levels of these small tags are critical for the correct functioning of cell division and one of our goals is to define which regulator controls which tag and when. Our work will help to unravel the control mechanisms that ensure correct distribution of the chromosomes and thus prevent aneuploidy. This knowledge will enable us to devise novel and better therapeutic approaches to cancer and further our understanding of other conditions where the chromosomes are not distributed correctly, e.g. birth defects.
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