title: Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes.
abstract: Analyses of chromosomal aberrations in human genetic disorders have revealed that inverted repeat sequences (IRs) often co-localize with endogenous chromosomal instability and breakage hotspots. Approximately 80% of all IRs in the human genome are short (<100 bp), yet the mutagenic potential of such short cruciform-forming sequences has not been characterized. Here, we find that short IRs are enriched at translocation breakpoints in human cancer and stimulate the formation of DNA double-strand breaks (DSBs) and deletions in mammalian and yeast cells. We provide evidence for replication-related mechanisms of IR-induced genetic instability and a novel XPF cleavage-based mechanism independent of DNA replication. These discoveries implicate short IRs as endogenous sources of DNA breakage involved in disease etiology and suggest that these repeats represent a feature of genome plasticity that may contribute to the evolution of the human genome by providing a means for diversity within the population.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin - Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard R1800, Austin, TX 78723, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Lu
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin - Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard R1800, Austin, TX 78723, USA.
authors.forename: Guliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin - Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard R1800, Austin, TX 78723, USA.
authors.forename: Albino
authors.initials: A
authors.lastname: Bacolla
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin - Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard R1800, Austin, TX 78723, USA.
authors.forename: Junhua
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin - Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard R1800, Austin, TX 78723, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Spitser
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin - Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard R1800, Austin, TX 78723, USA. Electronic address: karen.vasquez@austin.utexas.edu.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vasquez