Mismatch repair enhances convergent transcription-induced cell death at trinucleotide repeats by activating ATR

摘要: Trinucleotide repeat (TNR) expansion beyond a certain threshold results in some 20 incurable neurodegenerative disorders where disease anticipation positively correlates with length. Long TNRs typically display bias toward further during germinal transmission from parents to offspring, and then are highly unstable somatic tissues of affected individuals. Understanding mechanisms TNR instability will provide insights into pathogenesis. Previously, we showed that enhanced convergent transcription at long CAG tracks induces cell death via ATR activation. Components TC-NER (transcription-coupled nucleotide excision repair) RNaseH enzymes resolve RNA/DNA hybrids oppose death, whereas the MSH2 component MMR (mismatch enhances death. The exact role pathway transcription-induced repeats is not well understood. In this study, show siRNA knockdowns components-MSH2, MSH3, MLHI, PMS2, PCNA-reduce DNA toxicity. Furthermore, knockdown MSH2, MLH1, PMS2 significantly reduces frequency foci formation. These observations suggest proteins activate toxicity by modulating formation transcription.