Cells limit mutagenesis by dealing with DNA lesions behind the fork

Abstract

AbstractDNA lesions are a threat for genome stability. In order to cope with these lesions, cells have evolved lesion tolerance mechanisms: Translesion Synthesis (TLS) that allows the cell to insert a nucleotide directly opposite to the lesion, with the risk if introducing a mutation. Or error-free Damage Avoidance (DA) that uses homologous recombination to retrieve the genetic information from the sister chromatid.In this article, we investigate the timing of lesion bypass. We show that TLS can occur at the fork, rapidly after the encounter with the blocking lesion. But TLS can also occur behind the fork, at postreplicative gaps that are generated downstream of the lesion after repriming has occurred. We show that in this latter situation, TLS is reduced because it is in competition with the Damage Avoidance pathway. We also showed that EXO1 seems to modulate the size of the post-replicative gaps, that in turn modulate the balance between TLS and damage avoidance.