New insights into centromere structure

Osaka, Japan – The genetic material inside cells is organized into structures called chromosomes. The centromere is essential for the correct division of the chromosomes via interaction with spindle microtubules when cells divide and grow. Now, a study by researchers at Osaka University has clarified the structure of the centromeric region in chicken cells using a technique known as cryogenic electron microscopy (cryo-EM).

Cryo-EM freezes samples quickly to preserve and stabilize them, and then images them using collisions with electrons to reveal their structure. A complex of proteins called the “kinetochore” forms at the centromeric region, and this is essential for cells to divide correctly. The researchers were able to clarify a structural change to the kinetochore at the atomic level using cryo-EM analysis.

When DNA is condensed into chromosomes, it is coiled around a core made of proteins called histones to form a structure known as a nucleosome. The nucleosomes in the centromeric region contain a variant histone protein called CENP-A, which specifies the location of the centromere. However, the mechanisms by which CENP-A is deposited at the centromeres to correctly define their location were unknown until now.

The research team showed that during mitosis (the process of cell division), a protein called CENP-C binds CENP-A and acts as a scaffold for other kinetochore proteins. However, during interphase (the time when the cell is not dividing), a different protein called KNL2 binds to centromeres instead. “KNL2 contains a CENP-C-like motif and is a component of the Mis18 complex, a licensing factor for new CENP-A deposition,” explains lead authors of the study Honghui Jiang and Mariko Ariyoshi.

The team further revealed that this interaction between KNL2 and the centromere is required for new deposition of CENP-A during interphase, which in turn helps maintain the correct location of the centromere. “We also showed that CENP-C is phosphorylated during mitosis, and phosphorylated CENP-C excludes KNL2 from the KNL2–CENP-A complex,” explains senior author Tatsuo Fukagawa. This suggests that KNL2 binds to CENP-A through interphase, maintaining the location of the centromere until a phosphate molecule becomes bound to CENP-C as the cells reach mitosis. Then, CENP-C preferentially binds to CENP-A, allowing the formation of the kinetochore for cell division.

These new insights into the structure of the centromeric region will prove invaluable in advancing knowledge of cell division and growth. Proteins involved in cell division and the kinetochore are targets for anti-cancer drugs; therefore, this work will also contribute to the design of novel drugs for diseases such as cancer.

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The article, “The cryo-EM structure of the CENP-A nucleosome in complex with ggKNL2”, will be published in EMBO Journal at DOI: https://www.embopress.org/doi/10.15252/embj.2022111965

About Osaka University

Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.

Website: https://resou.osaka-u.ac.jp/en