Discussion

Genotoxic stress is a constant threat to the genome of any organism and if left unresolved, genome integrity becomes compromised. To this effect, cells have evolved numerous pathways to monitor, assess and ultimately control the outcome of genome lesions collectively referred to as the DNA Damage Response (DDR). Central to the DDR is the atypical protein kinase ATR which is predominantly activated in response to replicative lesions such as stalled replication forks. To date, the initiation of VSG switching has been linked to the generation of a direct double stranded break lesion within the active expression site to facilitate switching by recombination however evidence is accumulating that VSG switching may be linked to the generation of replicative lesions. Here, we show that loss of ATR in bloodstream form T.brucei parasites not only compromises cell proliferation and de-regulates the cell cycle but additionally results in the de-repression of silent VSG genes as confirmed by RNAseq analysis thus supporting a role for ATR during the regulation of VSG switching and the subsequent likely generation of replicative lesions as an initiation factor of VSG switching by recombination.