Structural and functional analysis of the yeast heterochromatin complex SIR

• Applicants: Professorin Dr. Ann Elizabeth Ehrenhofer-Murray; Professor Dr. Christian M. T. Spahn
• Subject Area: Structural Biology ; General Genetics and Functional Genome Biology ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523314628

The packaging of eukaryotic genomes into functionally distinct chromatin domains plays a crucial role in controlling all processes on DNA like replication, transcription, DNA repair and chromosome segregation. Large genomic regions assume a repressive structure termed heterochromatin, which is established by heterochromatin proteins that bind to the nucleosomes and inhibit transcription by yet unknown mechanisms. In higher eukaryotes, such regions typically are found at the telomeres, where they prevent degradation and recombination, and centromeres, where they are important for proper chromosome segregation. An archetypal form of heterochromatin is found in the budding yeast Saccharomyces cerevisiae at the silent mating-type loci HML and HMR, and at the telomeres. The establishment and formation of heterochromatin at these loci is mediated by the silent information regulator (SIR) complex, which consists of the NAD+-dependent histone deacetylase (HDAC) Sir2 and the components Sir3 and Sir4. A detailed mechanistic understanding of SIR-mediated repression requires molecular knowledge the complex. However, while information is available for individual parts of the SIR complex, a structure of the complete SIR complex is missing. In this project, the Ehrenhofer-Murray and Spahn labs aim to solve the structure of the SIR complex in its free form as well as when it is bound to nucleosomes. We will combine these structural aims with genetic experiments to assess the functional relevance of the structure(s) for silencing in yeast cells. This work will be of high relevance, because it will allow novel structural and mechanistic insights into how repression by the SIR complex is achieved.

• DFG Programme: Research Grants