Regulation of antigenic variation by a DOT1B/RNaseH2 complex in Trypanosoma brucei

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Post-translational modifications of chromatin regulate many important biological processes such as replication, DNA repair and cell cycle control. We are interested in how the unicellular, eukaryotic parasite Trypanosoma brucei uses chromatin-based mechanisms to regulate antigenic variation, one of its most important strategies to evade the host immune response. Antigenic variation is based on monoallelic expression of a variant surface glycoprotein (VSG), which forms a dense coat on the parasite’s surface. The parasites escape the host immune response by periodically switching the expressed VSG. The exact mechanisms, however, which mediate these switching events are still elusive.We are specifically interested in the function of histone methylation by a member of the Dot1 family of histone methyltransferases during this process. Dot1 (disruptor of telomeric silencing) was initially discovered in yeast in a genetic screen for genes whose over-expression or deletion caused derepression of telomeric genes. We recently discovered that DOT1B, one of the two homologues in trypanosomes, interacts with the ribonuclease RNaseH2 protein complex, which removes DNA/RNA-hybrids, so called R-loops. Interestingly, loss of RNaseH2 activity in trypanosomes causes accumulation of R-loops and DNA damage, which leads to altered VSG expression. We want to elucidate the function of the DOT1B/RNAseH2 complex in trypanosomes. In addition to general function in genome integrity maintenance, we specifically want to test the hypothesis that the DOT1B/RNAseH2 complex may be involved in VSG regulation.