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

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.
Authors	Nicholas R Pannunzio, Michael R Lieber
Journal	Molecular cell (Mol Cell) Vol. 68 Issue 5 Pg. 901-912.e3 (Dec 07 2017) ISSN: 1097-4164 [Electronic] United States
PMID	29220655 (Publication Type: Journal Article)
Copyright	Copyright © 2017 Elsevier Inc. All rights reserved.
Chemical References	DNA, Fungal DNA-Binding Proteins 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
Topics	Chromosomes, Human (chemistry, genetics, metabolism) Cytidine Deaminase (genetics, metabolism) DNA Breaks, Double-Stranded DNA, Fungal (chemistry, genetics, metabolism) DNA-Binding Proteins Endonucleases (genetics, metabolism) Gene Expression Regulation, Enzymologic Gene Expression Regulation, Fungal Humans Nucleic Acid Conformation Oxidative Stress Peroxidases (genetics, metabolism) Reactive Oxygen Species (metabolism) Saccharomyces cerevisiae (enzymology, genetics) Saccharomyces cerevisiae Proteins (genetics, metabolism) Structure-Activity Relationship Transcription, Genetic Translocation, Genetic Uracil-DNA Glycosidase (genetics, metabolism)

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