Damaged DNA replication: how Translesion synthesis (TLS) and Damage Avoidance (DA) pathways are interconnected in vivo?
|演題||Damaged DNA replication: how Translesion synthesis (TLS) and Damage Avoidance (DA) pathways are interconnected in vivo?|
|講演者||Robert P. Fuchs, CRCM, CNRS Marseille (France)
DNA Damage Tolerance (DDT) pathways allow cells to duplicate their genomes despite the presence of replication blocking lesions. Cells possess two major DDT strategies, namely Translesion Synthesis (TLS) and Damage Avoidance (DA). TLS pathways involve specialized DNA polymerases that are able to copy past DNA lesions with an intrinsic risk of introducing point mutations. In contrast, DA pathways rely on the sister chromatid to recover the missing genetic information via an error-free process that involves RecA. When a replication-blocking lesion impairs the progression of the replicative DNA polymerase, the single-stranded DNA RecA-filament that forms downstream from the lesion represents an early intermediate in the DA pathway. In order to investigate the interconnection between TLS and DA pathways in vivo, we analysed the DDT profiles for common replication blocking lesions in strains that are partially impaired in homologous recombination. Using two recA alleles that are partially defective in D-loop formation, but proficient in SOS induction, we observe a robust increase in TLS compared to the corresponding wild type strain. From these data we infer that the delay in D-loop formation, incurred in the recA strains, increases TLS by increasing the time frame during which the primer terminus is available for TLS. In good agreement with this hypothesis, strains delayed in RecA-filament formation due to a recF mutation also exhibit an increase in TLS for lesions that are bypassed by Pol II or Pol IV.
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