title: Mismatch repair enhances convergent transcription-induced cell death at trinucleotide repeats by activating ATR.
abstract: Trinucleotide repeat (TNR) expansion beyond a certain threshold results in some 20 incurable neurodegenerative disorders where disease anticipation positively correlates with repeat length. Long TNRs typically display a bias toward further expansion during germinal transmission from parents to offspring, and then are highly unstable in somatic tissues of affected individuals. Understanding mechanisms of TNR instability will provide insights into disease pathogenesis. Previously, we showed that enhanced convergent transcription at long CAG repeat tracks induces TNR instability and cell death via ATR activation. Components of TC-NER (transcription-coupled nucleotide excision repair) and RNaseH enzymes that resolve RNA/DNA hybrids oppose cell death, whereas the MSH2 component of MMR (mismatch repair) enhances cell death. The exact role of the MMR pathway during convergent transcription-induced cell death at CAG repeats is not well understood. In this study, we show that siRNA knockdowns of MMR components-MSH2, MSH3, MLHI, PMS2, and PCNA-reduce DNA toxicity. Furthermore, knockdown of MSH2, MLH1, and PMS2 significantly reduces the frequency of ATR foci formation. These observations suggest that MMR proteins activate DNA toxicity by modulating ATR foci formation during convergent transcription.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: nimratchatterjee@gmail.com.
authors.forename: Nimrat
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Wilson
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001483:Base Sequence; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D000070957:MutL Protein Homolog 1 / Q000172:deficiency / Q000235:genetics; D051718:MutS Homolog 2 Protein / Q000172:deficiency / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*; D018911:Trinucleotide Repeats
chemical_list: D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; D034741:RNA, Small Interfering; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: ATR DNA damage response; Cell death; Convergent transcription; Mismatch repair; Neurodegenerative diseases; Trinucleotide repeat instability