Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes

Steve Lu; Guliang Wang; Albino Bacolla; Junhua Zhao; Scott Spitser; Karen M Vasquez

doi:10.1016/j.celrep.2015.02.039

Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes

Cell Rep. 2015 Mar 17;10(10):1674-1680. doi: 10.1016/j.celrep.2015.02.039. Epub 2015 Mar 12.

Authors

Steve Lu¹, Guliang Wang¹, Albino Bacolla¹, Junhua Zhao¹, Scott Spitser¹, Karen M Vasquez²

Affiliations

¹ 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.
² 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.

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.

Abstract

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