Molecular Cell
Volume 68, Issue 5, 7 December 2017, Pages 901-912.e3
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Article
AID and Reactive Oxygen Species Can Induce DNA Breaks within Human Chromosomal Translocation Fragile Zones

https://doi.org/10.1016/j.molcel.2017.11.011Get rights and content
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Highlights

  • New insight into transcription as a cause of increased DNA double-strand breaks

  • Topoisomerase loss sensitizes DNA to AID and to increased oxidative stress

  • Oxidative stress and AID highlight novel pathways for chromosome breaks

  • Long-lived DNA lesions in human fragile zones are a critical cause of DSBs

Summary

DNA double-strand breaks (DSBs) occurring within fragile zones of less than 200 base pairs account for the formation of the most common human chromosomal translocations in lymphoid malignancies, yet the mechanism of how breaks occur remains unknown. Here, we have transferred human fragile zones into S. cerevisiae in the context of a genetic assay to understand the mechanism leading to DSBs at these sites. Our findings indicate that a combination of factors is required to sensitize these regions. Foremost, DNA strand separation by transcription or increased torsional stress can expose these DNA regions to damage from either the expression of human AID or increased oxidative stress. This damage causes DNA lesions that, if not repaired quickly, are prone to nuclease cleavage, resulting in DSBs. Our results provide mechanistic insight into why human neoplastic translocation fragile DNA sequences are more prone to enzymes or agents that cause longer-lived DNA lesions.

Keywords

human lymphoma chromosomal translocation fragile zones
S. cerevisiae
DNA double-strand break
non-B DNA
transcription
oxidative stress
torsional stress
Artemis
activation-induced deaminase
slipped-strand DNA

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