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

•Short inverted repeat (IR) sequences are enriched at human cancer breakpoints•Short IRs stimulate DNA double-strand breaks and deletions in mammalian cells•Short IRs impede DNA replication forks in mammalian cells•ERCC1-XPF cleaves IRs and is required for IR-induced chromosome breakage

SummaryAnalyses 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.

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