期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 431, 期 10, 页码 2040-2049出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2019.03.011
关键词
DNA replication; DNA damage response; DNA repair; replication fork; stalled fork
资金
- Medical Research Council [MC_UP_1201/12]
- Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust [110014/Z/15/Z]
- Wellcome Trust [110014/Z/15/Z] Funding Source: Wellcome Trust
- MRC [MC_UP_1201/12] Funding Source: UKRI
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.
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