title: Environmental stress induces trinucleotide repeat mutagenesis in human cells.
abstract: 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 human diseases-have revealed a remarkable complexity of mutagenic mechanisms. Here, we show that cold, heat, hypoxic, and oxidative stresses induce mutagenesis of a long CAG repeat tract in human 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, nucleotide excision repair, or transcription, processes that are known to promote TNR 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 CDT1 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 TNR 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.
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology and.
authors.forename: Nimrat
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology and.
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Beatriz A
authors.initials: BA
authors.lastname: Santillan
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital, Houston, TX 77030.
authors.forename: Patricia
authors.initials: P
authors.lastname: Yotnda
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; jwilson@bcm.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Wilson
mesh_terms: D003080:Cold Temperature; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004260:DNA Repair; D004261:DNA Replication; D053263:Gene Regulatory Networks; D042822:Genomic Instability; D049452:Green Fluorescent Proteins / Q000737:chemistry; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D018895:Microsatellite Repeats; D016296:Mutagenesis; D018384:Oxidative Stress; D010641:Phenotype; D013312:Stress, Physiological; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: D049452:Green Fluorescent Proteins; D004247:DNA
keywords: DNA rereplication; human cells; microsatellite repeats; stress-induced mutagenesis; trinucleotide repeats