Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes
Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en favorisant une instabilité génomique, de petites séquences d'ADN organisées en répétitions inversées sont susceptibles d'induire la formation d'une tumeur
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.
http://www.cell.com/cell-reports/abstract/S2211-1247(15)00197-7