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Review

Mechanisms for stalled replication fork stabilization: new targets for synthetic lethality strategies in cancer treatments

Hongwei Liao, Fang Ji, View ORCID ProfileThomas Helleday, View ORCID ProfileSongmin Ying
DOI 10.15252/embr.201846263 | Published online 13.08.2018
EMBO reports (2018) e46263
Hongwei Liao
Department of Pharmacology & Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China
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Fang Ji
Department of Pharmacology & Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China
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Thomas Helleday
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, SwedenSheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
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Songmin Ying
Department of Pharmacology & Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China
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Author Affiliations

  1. Hongwei Liao1,
  2. Fang Ji1,
  3. Thomas Helleday (t.helleday{at}sheffield.ac.uk)*,2,3 and
  4. Songmin Ying (yings{at}zju.edu.cn)*,1
  1. 1Department of Pharmacology & Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital, Institute of Respiratory Diseases, Zhejiang University School of Medicine, Hangzhou, China
  2. 2Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
  3. 3Sheffield Cancer Centre, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
  1. ↵* Corresponding author. Tel: +46 8 524 800 00; E‐mail: t.helleday{at}sheffield.ac.uk
    Corresponding author. Tel: +86 0571 88208059; E‐mail: yings{at}zju.edu.cn
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Abstract

Timely and faithful duplication of the entire genome depends on completion of replication. Replication forks frequently encounter obstacles that may cause genotoxic fork stalling. Nevertheless, failure to complete replication rarely occurs under normal conditions, which is attributed to an intricate network of proteins that serves to stabilize, repair and restart stalled forks. Indeed, many of the components in this network are encoded by tumour suppressor genes, and their loss of function by mutation or deletion generates genomic instability, a hallmark of cancer. Paradoxically, the same fork‐protective network also confers resistance of cancer cells to chemotherapeutic drugs that induce high‐level replication stress. Here, we review the mechanisms and major pathways rescuing stalled replication forks, with a focus on fork stabilization preventing fork collapse. A coherent understanding of how cells protect their replication forks will not only provide insight into how cells maintain genome stability, but also unravel potential therapeutic targets for cancers refractory to conventional chemotherapies.

  • fork stabilization
  • synthetic lethality
  • PARP inhibitors

EMBO Reports (2018) e46263

  • Received April 12, 2018.
  • Revision received July 6, 2018.
  • Accepted July 20, 2018.
  • © 2018 The Authors
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In this Issue
Volume 20, Issue 2
01 February 2019
EMBO reports: 20 (2)
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Article

  • Article
    • Abstract
    • Introduction
    • ssDNA protection
    • Fork reversal
    • Protection against nucleolytic degradation
    • Checkpoint activation
    • Exploiting fork instability in cancer treatment
    • Concluding remarks
    • Conflict of interest
    • Acknowledgements
    • Footnotes
    • References
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