Environmental Stress Induces Trinucleotide Repeat Mutagenesis in Human Cells by Alt-Nonhomologous End Joining Repair.
Multiple pathways modulate the dynamic mutability of trinucleotide repeats (TNRs), which are implicated in neurodegenerative disease and evolution. Recently, we reported that environmental stresses induce TNR mutagenesis via stress responses and rereplication, with more than 50% of mutants carrying deletions or insertions-molecular signatures of DNA double-strand break repair. We now show that knockdown of alt-nonhomologous end joining (alt-NHEJ) components-XRCC1, LIG3, and PARP1-suppresses stress-induced TNR mutagenesis, in contrast to the components of homologous recombination and NHEJ, which have no effect. Thus, alt-NHEJ, which contributes to genetic mutability in cancer cells, also plays a novel role in environmental stress-induced TNR mutagenesis.
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: nimratc@mit.edu.
Nimrat
N
Chatterjee
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Yunfu
Y
Lin
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
Patricia
P
Yotnda
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
John H
JH
Wilson
D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D016296:Mutagenesis / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*
alt-nonhomologous end joining (alt-NHEJ); double-strand break repair (DSBR); environmental stress; mutagenesis; trinucleotide repeats