The ATR kinase of Trypanosoma brucei links DNA damage signalling during antigenic variation with regulation of RNA Polymerase I transcribed surface antigens

Trypanosoma brucei evades mammalian immunity by using recombination to switch its surface expressed Variant Surface Glycoprotein (VSG), whilst ensuring only one of many subtelomeric multigene VSG expression sites are transcribed at a time. DNA repair activities have been implicated only in catalysis of VSG switching by recombination, not transcriptional control. How VSG switching is signalled to guide the appropriate reaction, or to integrate switching into parasite growth, is unknown. Here we show that loss of ATR, a DNA damage signalling protein kinase, is lethal, causing nuclear genome instability and increased VSG switching through VSG-localised damage. Furthermore, ATR loss leads to increased transcription of silent VSG expression sites and expression of mixed VSGs on the cell surface, effects that are associated with altered localisation of RNA Polymerase I and VEX1. This work therefore reveals that ATR acts in antigenic variation both through DNA damage signalling and surface antigen expression control.