Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigen

TY - JOUR

T1 - Trypanosoma brucei ATR Links DNA Damage Signaling during Antigenic Variation with Regulation of RNA Polymerase I-Transcribed Surface Antigen

AU - Black, Jennifer Ann

AU - Crouch, Kathryn

AU - Lemgruber, Leandro

AU - Lapsley, Craig

AU - Dickens, Nicholas J

AU - Tosi, Luiz R O

AU - Mottram, Jeremy Charles

AU - McCulloch, Richard

N1 - © 2019 The Author(s)

PY - 2020/1/21

Y1 - 2020/1/21

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2019.12.049

DO - 10.1016/j.celrep.2019.12.049

M3 - Article

VL - 30

SP - 836

EP - 851

JO - Cell reports

JF - Cell reports

SN - 2211-1247

IS - 3

M1 - e5

ER -