Dynamics of Replication Fork Progression Following Helicase-Polymerase Uncoupling in Eukaryotes.

ABSTRACT: Leading-strand polymerase stalling at DNA damage impairs replication fork progression. Using biochemical approaches, we show this arises due to both slower template unwinding following helicase-polymerase uncoupling and establishment of prolonged stalled fork structures. Fork slowing and stalling occur at structurally distinct lesions, are always associated with continued lagging-strand synthesis, are observed when either Pol ? or Pol ? stalls at leading-strand damage, and do not require specific helicase-polymerase coupling factors. Hence, the key trigger for these replisome-intrinsic responses is cessation of leading-strand polymerization, revealing this as a crucial driver of normal replication fork rates. We propose that this helps balance the need for sufficient uncoupling to activate the DNA replication checkpoint with excessive destabilizing single-stranded DNA exposure in eukaryotes.

SUBMITTER: Taylor MRG 

PROVIDER: S-EPMC6525111 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature