Unraveling the mechanism of DOT1A-mediated replication regulation in Trypanosoma brucei

• Applicant: Professor Dr. Christian Janzen
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Cell Biology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 266162548

Post-translational histone modifications regulate many important biological processes like replication, DNA repair and cell cycle control. We use the unicellular, eukaryotic parasite Trypanosoma brucei as a model system to study how replication regulation and developmental differentiation are controlled by chromatin-based mechanisms. We are specifically interested in the function of histone H3 methylation by a member of the Dot1 family of lysine methyltransferases. Dot1 (disruptor of telomeric silencing, also called KMT4) was initially discovered in yeast in a genetic screen for genes whose over-expression caused defects in telomeric silencing. In the previous funding period, we wanted to unravel the function of chromatin structure during cell cycle regulation and developmental differentiation in T. brucei. In the course of these projects, we began to focus on the function of two trypanosome Dot1 homologues DOT1A and DOT1B, which are responsible for di-methylation and tri-methylation of H3K76, respectively. Surprisingly, we discovered that DOT1A-mediated H3K76 mono- or di-methylation regulates replication initiation. This is a novel regulatory mechanism for replication in eukaryotes, which was also described in human cells shortly after we published our results. Based on this successful initial project, we now aim to unravel the mechanistic events behind this cellular process. We plan to identify the molecular machinery, which mediates H3K76 methylation-dependent regulation of replication to learn more about this basic biological process.

• DFG Programme: Research Grants