Journal article
Tracking break-induced replication shows that it stalls at roadblocks
Nature (London), Vol.590(7847), pp.655-659
02/2021
DOI: 10.1038/s41586-020-03172-w
PMCID: PMC8219245
PMID: 33473214
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 diseases
. Previous studies have defined the enzymes that are required for BIR
; 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.
Details
- Title: Subtitle
- Tracking break-induced replication shows that it stalls at roadblocks
- Creators
- Liping Liu - Department of Biology, University of Iowa, Iowa City, IA, USAZhenxin Yan - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USABeth A Osia - Department of Biology, University of Iowa, Iowa City, IA, USAJerzy Twarowski - Department of Biology, University of Iowa, Iowa City, IA, USALuyang Sun - Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USAJuraj Kramara - Department of Biology, University of Iowa, Iowa City, IA, USARosemary S Lee - Department of Biology, University of Iowa, Iowa City, IA, USASandeep Kumar - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USARajula Elango - Department of Medicine, Division of Hematology-Oncology and Cancer Research Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USAHanzeng Li - Department of Internal Medicine, University of Iowa, Iowa City, IA, USAWeiwei Dang - Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USAGrzegorz Ira - Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. gira@bcm.eduAnna Malkova - Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, IA, USA. anna-malkova@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.590(7847), pp.655-659
- DOI
- 10.1038/s41586-020-03172-w
- PMID
- 33473214
- PMCID
- PMC8219245
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Language
- English
- Date published
- 02/2021
- Academic Unit
- Stead Family Department of Pediatrics; Biology; Infectious Disease (Pediatrics); Internal Medicine
- Record Identifier
- 9984217412002771
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