Tracking break-induced replication shows that it stalls at roadblocks

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 () and Anna Malkova ()
Additional contact information
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
Juraj Kramara: University of Iowa
Rosemary S. Lee: University of Iowa
Sandeep Kumar: Baylor College of Medicine
Rajula Elango: University of Iowa
Hanzeng Li: University of Iowa
Weiwei Dang: Baylor College of Medicine
Grzegorz Ira: Baylor College of Medicine
Anna Malkova: University of Iowa

Nature, 2021, vol. 590, issue 7847, 655-659

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-020-03172-w

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