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

JOURNAL OF MOLECULAR BIOLOGY

卷:431

Article

Taylor, Martin R. G.¹  Yeeles, Joseph T. P.¹ 

[1] Med Res Council Lab Mol Biol, Div Prot & Nucle Acid Chem, Francis Crick Ave, Cambridge CB2 0QH, England

关键词: DNA replication;    DNA damage response;    DNA repair;    replication fork;    stalled fork;   

DOI  :  10.1016/j.jmb.2019.03.011

来源: Elsevier

【 摘 要 】

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 epsilon or Pol delta 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. (C) 2019 MRC Laboratory of Molecular Biology. Published by Elsevier Ltd.

【 授权许可】

Free