Research on centromere structure yields new insights into the mechanisms of chromosome segregation errors

Our bodies consist of trillions of cells, most of which have a limited life span and therefore need to reproduce to replace the old ones. This reproduction process is referred to as cell division or mitosis. During mitosis, the parent cell will duplicate its chromosomesA stretch of DNA that forms long, tightly twisted strains in the nucleus of the cell, together with proteins. The cells of most human have 46 chromosomes, divided over 23 pairs: 23 from your mother and 23 from your father. in order to pass down the genetic material to the daughter cells. The resulting identical pairs of chromosomes, the sister chromatids, are held together by a structure called the centromere. The sister chromatids then need to be evenly split over the two daughter cells to ensure that each daughter cell is an exact copy of the parent cell. If errors happen during the segregation, one daughter cell will have too many chromosomes, while the other has too few. This can lead to cell death or cancer development.

The role of the centromere

The centromere is a part of the chromosome that plays a vital role in chromosome segregation during mitosis. The process of dividing the sister chromatids over the cells is guided by the interaction between the centromeres and structures known as spindle microtubules. These spindle microtubules are responsible for pulling the chromatids apart and thus separating the two sister chromatids. Carlos Sacristan Lopez, the first author of this study, explains: ‘If the attachment of the centromere to the spindle microtubules does not occur properly it leads to chromosome segregation mistakes which are frequently observed in cancer.’ Understanding the structure of the centromere can contribute to more insights into the function of the centromere and its role in erroneous chromosomal segregation.

A surprising discovery

To investigate the centromere structure, the researchers used a combination of imaging and sequencingA technique that is used by researchers to determine the genetic code of DNA or RNA. This information can be used in various ways. In disease research, sequencing may be used to trace changes in the genetic code. This could for example elucidate the cause of the disease. techniques. The super-resolution microscopy imaging took place at the Hubrecht Institute, while the group of Bill Earnshaw performed the sequencing. This collaboration led to a surprising new discovery in the centromere structure. Previously believed to consist of a compact structure attaching to multiple spindle microtubules, it was instead revealed that the centromere consists of two subdomains. Carlos explains: ‘This discovery was very surprising, as subdomains bind microtubules independently of each other. Yet, to form correct attachments, they must remain closely connected. In cancer cells, however, we often observe that subdomains uncouple, resulting in erroneous attachments and chromosome segregation errors.’

This very exciting and fundamental discovery contributes to our understanding of the origin of chromosome segregation errors which are frequently seen in cancer.

Publication

Vertebrate centromeres in mitosis are functionally bipartite structures stabilized by cohesin. Carlos Sacristan, Kumiko Samejima, Lorena Andrade Ruiz, Moonmoon Deb, Maaike L.A. Lambers, Adam Buckle, Chris A. Brackley, Daniel Robertson, Tetsuya Hori, Shaun Webb, Robert Kiewisz, Tristan Bepler, Eloïse van Kwawegen, Patrik Risteski, Kruno Vukušić, Iva M. Tolić, Thomas Müller-Reichert, Tatsuo Fukagawa, Nick Gilbert, Davide Marenduzzo, William C. Earnshaw, and Geert J.P.L. Kops