R loops stimulate genetic instability of CTG center dot CAG repeats

Lin YF; Dent SYR; Wilson JHWells RDNapierala M

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R loops stimulate genetic instability of CTG center dot CAG repeats

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Transcription stimulates the genetic instability of trinucleotide repeat sequences. However, the mechanisms leading to transcription-dependent repeat length variation are unclear. We demonstrate, using biochemical and genetic approaches, that the formation of stable RNA . DNA hybrids enhances the instability of CTG . CAG repeat tracts. In vitro transcribed CG-rich repeating sequences, unlike AT-rich repeats and nonrepeating sequences, form stable, ribonuclease A-resistant structures. These RNA . DNA hybrids are eliminated by ribonuclease H treatment. Mutation in the rnhA1 gene that decreases the activity of ribonuclease HI stimulates the instability of CTG . CAG repeats in E. coli. Importantly, the effect of ribonuclease HI depletion on repeat instability requires active transcription. We also showed that transcription-dependent CTG . CAG repeat instability in human cells is stimulated by siRNA knockdown of RNase H1 and H2. In addition, we used bisulfite modification, which detects single-stranded DNA, to demonstrate that the nontemplate DNA strand at transcribed CTG . CAG repeats remains partially single-stranded in human genomic DNA, thus indicating that it is displaced by an RNA . DNA hybrid. These studies demonstrate that persistent hybrids between the nascent RNA transcript and the template DNA strand at CTG . CAG tracts promote instability of DNA trinucleotide repeats.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第2期|692-697|共6页
作者
Lin YF; Dent SYR; Wilson JHWells RDNapierala M;
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作者单位

Baylor College of Medicine, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, One Baylor Plaza, Houston, TX 77030;

University of Texas M. D. Anderson Cancer Center, Department of Biochemistry and Molecular Biology and Center for Cancer Epigenetics,1515 Holcombe Boulevard, Houston, TX 77030;

Center for Genome Research, Institute of Biosciences and Technology,Texas A&M Health Science Center, 2121 West Holcombe Boulevard, Houston, TX 77030;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
RNA·DNA hybrids; transcription-induced instability; triplet repeats;

R loops stimulate genetic instability of CTG center dot CAG repeats

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