Browsing by Subject "pharmacology and toxicology"
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Item Short inverted repeats are hot spots for genetic instability in mammalian cells(2012) Lu, Steve; Vasquez, Karen M.; Laude, DavidAnalyses of chromosomal aberrations in genetics disorders such as leukemia and lymphoma have provided compelling evidence that segments of the human genome containing repetitive sequences can be prone to breakage and chromosomal rearrangements. While long inverted repeat (IR) sequences have been shown to be mutagenic in mammalian cells, the mutagenic potential of short IR sequences (<30 bp), which are very abundant in eukaryotic genomes and often co-localize near chromosomal breakpoints, has not been investigated. Herein, we demonstrate that cruciform structures formed at short perfect IRs are mutagenic in mammalian cells. We found that DNA double-strand breaks (DSBs) occurred in vivo at or near the IR sequences, and the majority of the mutations induced by short IRs were large-scale deletions spanning the palindromic sequence. Analyses of the mutant junctions revealed that ~80% contained microhomologies, which are characteristic of an error-prone microhomology-mediated end-joining repair mechanism. We found that cruciform-induced mutations and DNA strand breaks may occur through 1) a replication-dependent mechanism involving DNA replication fork stalling or 2) replication-independent, structure-specific enzymes that facilitate cleavage at positions adjacent to the IR sequences. Taken together, our results demonstrate that short inverted repeat sequences play a role in genetic instability, and provide a plausible mechanistic explanation for the co-localization of IRs with chromosome breakage points in human disease. These findings also support the hypothesis that alternatively structured DNA is a feature of genome plasticity and may be a contributor to human disease and a driving force in the evolution of the human genome by providing a means for diversity within the population.