کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2042032 | 1073183 | 2015 | 7 صفحه PDF | دانلود رایگان |
• 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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Journal: - Volume 10, Issue 10, 17 March 2015, Pages 1674–1680