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.

Fanconi anemia pathway regulates convergent transcription-induced cell death at trinucleotide repeats in human cells

“…Transcription induction at both the sense and antisense promoters causes a synergistic increase in cell death at diverse TNRs, triggered by an activated ATR DNA damage response [18, 19, 39]. DNA repair pathways modulate this DNA toxicity effect, with an additional role of mismatch repair (MMR) pathway in regulating ATR activation during convergent transcription [13, 28]. …”

“…Additionally, we found that TC-NER and R-loop resolution enzymes lower DNA toxicity of convergent transcription, whereas MMR components increase cell death by activating ATR DNA damage response during convergent transcription [25-28]. Because activated ATR is an important trigger for the Fanconi anemia (FA) pathway to repair interstrand DNA crosslinks [29], we asked whether FA components could also modulate convergent-transcription-induced cell death at CAG repeats.…”

Mechanisms of DNA damage, repair, and mutagenesis

“…Typical substrates for the MMR pathway are base mismatches that have arisen during replication and the insertion‐deletion loops (IDLs) within repetitive DNA sequences that have resulted from strand slippage events [Errol C. Friedberg, 2005; Jiricny, ]. MMR is also implicated in a variety of cellular processes including microsatellite stability, meiotic and mitotic recombination, DNA‐damage signaling, apoptosis, class‐switch recombination, somatic hypermutation, and triplet‐repeat expansion [Jiricny, ; Jiricny, ; Chatterjee et al, ]. Germline mutations in the MMR genes result in Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), which presents as a familial susceptibility to colon and ovarian cancers as well to a number of other cancers [Peltomaki, ].…”

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

“…In addition to intergenerational instability, tissue‐specific mosaicism has been observed in polyQ diseases, resulting in cell populations carrying different CAG repeat lengths, within or between tissues . This CAG repeat instability underlies some features of polyQ disorders and may also contribute to their pathogenic mechanism …”