Abstract

The cellular pathways that restart stalled replication forks are essential for genome stability and tumor prevention. However, how many of these pathways exist in cells and how these pathways are selectively activated remain unclear. Here, we describe two major fork restart pathways, and demonstrate that their selection is governed by 53BP1 and BRCA1, which are known to control the pathway choice to repair double-strand DNA breaks (DSBs). Specifically, 53BP1 promotes a fork cleavage-free pathway, whereas BRCA1 facilitates a break-induced replication (BIR) pathway coupled with SLX-MUS complex-mediated fork cleavage. The defect in the first pathway, but not DSB repair, in a 53BP1 mutant is largely corrected by disrupting BRCA1, and vice versa. Moreover, PLK1 temporally regulates the switch of these two pathways through enhancing the assembly of the SLX-MUS complex. Our results reveal two distinct fork restart pathways, which are antagonistically controlled by 53BP1 and BRCA1 in a DSB repair-independent manner.

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Author details

  1. Yixi Xu

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Shaokai Ning

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Zheng Wei

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Ran Xu

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Xinlin Xu

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Mengtan Xing

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Rong Guo

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    For correspondence
    guorong@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  8. Dongyi Xu

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    For correspondence
    xudongyi@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5711-2618

Funding

National Basic Research Program of China (2013CB911002)

  • Dongyi Xu

National Natural Science Foundation of China (81672773)

  • Dongyi Xu

National Natural Science Foundation of China (31661143040)

  • Dongyi Xu

National Natural Science Foundation of China (31370836)

  • Rong Guo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrés Aguilera, CABIMER, Universidad de Sevilla, Spain

Version history

  1. Received: July 18, 2017
  2. Accepted: November 4, 2017
  3. Accepted Manuscript published: November 6, 2017 (version 1)
  4. Version of Record published: November 13, 2017 (version 2)
  5. Version of Record updated: January 2, 2018 (version 3)

Copyright

© 2017, Xu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yixi Xu
  2. Shaokai Ning
  3. Zheng Wei
  4. Ran Xu
  5. Xinlin Xu
  6. Mengtan Xing
  7. Rong Guo
  8. Dongyi Xu
(2017)
53BP1 and BRCA1 control pathway choice for stalled replication restart
eLife 6:e30523.
https://doi.org/10.7554/eLife.30523

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https://doi.org/10.7554/eLife.30523

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