Role of lysine deacetylase Hst2 in mitotic chromosome condensation

• Applicant: Professor Dr. Heinz Neumann
• Subject Area: General Genetics and Functional Genome Biology ; Biochemistry ; Cell Biology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 299532777

Mitotic chromosomes are characteristic hallmarks of cell division. However, till date have their molecular structure, their composition and the mechanisms leading to their formation remained largely mysterious. Biochemical analyses are hampered by the stickiness of chromatin, attracting large numbers of unspecific binding proteins, and the dynamic changes in its structure in response to changing environmental conditions. Using an in vivo crosslinking approach with genetically installed unnatural amino acids my lab has identified a cascade of histone modifications that initiates the condensation of chromatin at the onset of mitosis. This revealed an entirely new mechanistic aspect of mitotic chromosome condensation independent and parallel to the canonical condensin machinery. A key player in this cascade is lysine deacetylase Hst2, which is recruited to chromatin by phosphorylation of the histone H3 tail. It mediates the removal of an acetylation from histone H4 tail to facilitate its interaction with neighbouring nucleosomes. This adds a driving force to chromosome condensation. In this proposal we want to analyse the details of the recruitment of Hst2 by searching for further interaction partners of the enzyme. We also expect to find additional deacetylation substrates for the enzymes because our preliminary results indicate the H4 deacetylation is not its only task in the condensation process. Finally, we want to reconstitute aspects of the condensation process in vitro to analyse its kinetic properties. From this project we want to get a detailed mechanistic understanding of how Hst2 coordinates chromosome condensation. This mechanism is likely conserved across all eukaryotes and may eventually become a target for the design of new therapeutic strategies in the treatment of cancer.

• DFG Programme: Research Grants