AID and Reactive Oxygen Species Can Induce DNA Breaks within Human Chromosomal Translocation Fragile Zones

Mol Cell. 2017 Dec 7;68(5):901-912.e3. doi: 10.1016/j.molcel.2017.11.011.

Abstract

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

MeSH terms

  • Chromosomes, Human / chemistry
  • Chromosomes, Human / genetics*
  • Chromosomes, Human / metabolism
  • Cytidine Deaminase / genetics*
  • Cytidine Deaminase / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA, Fungal / chemistry
  • DNA, Fungal / genetics*
  • DNA, Fungal / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Fungal
  • Humans
  • Nucleic Acid Conformation
  • Oxidative Stress*
  • Peroxidases / genetics
  • Peroxidases / metabolism
  • Reactive Oxygen Species / metabolism*
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Structure-Activity Relationship
  • Transcription, Genetic
  • Translocation, Genetic*
  • Uracil-DNA Glycosidase / genetics
  • Uracil-DNA Glycosidase / metabolism

Substances

  • DNA, Fungal
  • Reactive Oxygen Species
  • Saccharomyces cerevisiae Proteins
  • Peroxidases
  • Tsa1 protein, S cerevisiae
  • DCLRE1C protein, human
  • Endonucleases
  • Uracil-DNA Glycosidase
  • AICDA (activation-induced cytidine deaminase)
  • Cytidine Deaminase