Environmental stress induces trinucleotide repeat mutagenesis in XXXX cells.

@entity1 @entity377 @entity27473 @entity519 @entity31423
UNASSIGNED: The dynamic mutability of microsatellite repeats is implicated in the modification of gene function and disease phenotype. Studies of the enhanced instability of long trinucleotide repeats (TNRs)-the cause of multiple @entity1 diseases-have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, @entity519 , and oxidative stresses induce mutagenesis of a long CAG repeat tract in @entity1 cells. We show that stress-response factors mediate the stress-induced mutagenesis (SIM) of CAG repeats. We show further that SIM of CAG repeats does not involve mismatch repair, @entity377 excision repair, or transcription, processes that are known to promote @entity31423 mutagenesis in other pathways of instability. Instead, we find that these stresses stimulate DNA rereplication, increasing the proportion of cells with >4 C-value (C) DNA content. Knockdown of the replication origin-licensing factor @entity27473 eliminates both stress-induced rereplication and CAG repeat mutagenesis. In addition, direct induction of rereplication in the absence of stress also increases the proportion of cells with >4C DNA content and promotes repeat mutagenesis. Thus, environmental stress triggers a unique pathway for @entity31423 mutagenesis that likely is mediated by DNA rereplication. This pathway may impact normal cells as they encounter stresses in their environment or during development or abnormal cells as they evolve metastatic potential.
