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Elucidation of the mechanism of sister Chromatid Cohesion

Final Activity Report Summary - CHROMOSOME STABILITY (Elucidation of the mechanism of sister Chromatid Cohesion)

Cells, the basic building blocks of all living organisms, each contain the genetic material, DNA, which is the blueprint for life. When cells divide, the mother cell's DNA, which is packaged into larger pieces called chromosomes, is duplicated in a process known as replication. This produces two identical copies of the DNA, named sister chromatids, which must then be equally divided between the two new daughter cells. If mistakes are made in this process, the daughter cells will abnormally gain or lose chromosomes, thus changing the genetic blueprint of the cells. With an incomplete or incorrect set of instructions, the cells will grow in an uncontrolled manner, which is the hallmark of cancer. To avoid such mistakes, a ring-like protein complex called cohesin holds the sister chromatids together until they are properly aligned and are ready for division between the daughter cells.

Cohesin is found at distinct places along the chromosomes. The location of cohesin changes, and the DNA sequence does not determine its placement. Because cohesin is shaped like a ring, cohesin may hold the two sister chromatids together by encircling them, and changes in cohesin localisation may arise from the cohesin ring sliding along the DNA. My goal during this fellowship was to define the rules that regulate how cohesin and DNA interact with each other and to understand what other factors may influence cohesin's ability to safely and securely hold sister chromatids together. To do this, I have used yeast as a model, since a process as fundamental as chromosome stability follows the same rules in yeast cells as in humans.

So far, we have learned that sliding rather than new loading is responsible for the repositioning of cohesin. Also, a number of factors, such as the cohesin loader protein, which are implicated in dynamic cohesin binding, are not required for cohesin association with chromosomes during translocation. Finally, there is a strong correlation between cohesin repositioning and transcription, since changing the site of transcriptional termination also alters cohesin localisation. By continuing to study how cohesin interacts with DNA, we will gain important insights about the processes that safeguard and promote healthy cell growth. When cohesion is defective, chromosomes are incorrectly separated and unequally divided between the daughter cells. This causes errors in the genetic blueprint, which deregulates the cell's normal function and allows cells to grow abnormally. Since aneuploidy, the abnormal loss or gain of chromosomes, is a common feature of malignant tumours and is linked to numerous congenital birth defects, our research will provide important insights about maintenance of genomic integrity and will have significant implications for diseases caused by chromosomal instabilities.