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Tracking break-induced replication shows that it stalls at roadblocks

Author

Listed:
  • Liping Liu

    (University of Iowa)

  • Zhenxin Yan

    (Baylor College of Medicine)

  • Beth A. Osia

    (University of Iowa)

  • Jerzy Twarowski

    (University of Iowa)

  • Luyang Sun

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Juraj Kramara

    (University of Iowa)

  • Rosemary S. Lee

    (University of Iowa)

  • Sandeep Kumar

    (Baylor College of Medicine)

  • Rajula Elango

    (University of Iowa
    Beth Israel Deaconess Medical Center and Harvard Medical School)

  • Hanzeng Li

    (University of Iowa)

  • Weiwei Dang

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Grzegorz Ira

    (Baylor College of Medicine)

  • Anna Malkova

    (University of Iowa
    University of Iowa)

Abstract

Break-induced replication (BIR) repairs one-ended double-strand breaks in DNA similar to those formed by replication collapse or telomere erosion, and it has been implicated in the initiation of genome instability in cancer and other human diseases1,2. Previous studies have defined the enzymes that are required for BIR1–5; however, understanding of initial and extended BIR synthesis, and of how the migrating D-loop proceeds through known replication roadblocks, has been precluded by technical limitations. Here we use a newly developed assay to show that BIR synthesis initiates soon after strand invasion and proceeds more slowly than S-phase replication. Without primase, leading strand synthesis is initiated efficiently, but is unable to proceed beyond 30 kilobases, suggesting that primase is needed for stabilization of the nascent leading strand. DNA synthesis can initiate in the absence of Pif1 or Pol32, but does not proceed efficiently. Interstitial telomeric DNA disrupts and terminates BIR progression, and BIR initiation is suppressed by transcription proportionally to the transcription level. Collisions between BIR and transcription lead to mutagenesis and chromosome rearrangements at levels that exceed instabilities induced by transcription during normal replication. Together, these results provide fundamental insights into the mechanism of BIR and how BIR contributes to genome instability.

Suggested Citation

  • Liping Liu & Zhenxin Yan & Beth A. Osia & Jerzy Twarowski & Luyang Sun & Juraj Kramara & Rosemary S. Lee & Sandeep Kumar & Rajula Elango & Hanzeng Li & Weiwei Dang & Grzegorz Ira & Anna Malkova, 2021. "Tracking break-induced replication shows that it stalls at roadblocks," Nature, Nature, vol. 590(7847), pages 655-659, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7847:d:10.1038_s41586-020-03172-w
    DOI: 10.1038/s41586-020-03172-w
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    Cited by:

    1. S. Cohen & A. Guenolé & I. Lazar & A. Marnef & T. Clouaire & D. V. Vernekar & N. Puget & V. Rocher & C. Arnould & M. Aguirrebengoa & M. Genais & N. Firmin & R. A. Shamanna & R. Mourad & V. A. Bohr & V, 2022. "A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Yi-Li Feng & Qian Liu & Ruo-Dan Chen & Si-Cheng Liu & Zhi-Cheng Huang & Kun-Ming Liu & Xiao-Ying Yang & An-Yong Xie, 2022. "DNA nicks induce mutational signatures associated with BRCA1 deficiency," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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