ArticleThe Journal of biological chemistry2020
R-loops promote trinucleotide repeat deletion through DNA base excision repair enzymatic activities.
Article in The Journal of biological chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Base excision repair within structure-forming repeat sequences and its impact on cancer and other diseases.NAR cancer · 2025Review
- RNA/DNA-binding protein TDP43 regulates DNA mismatch repair genes with implications for genome stability.Nucleic acids research · 2025Article
- RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.bioRxiv : the preprint server for biology · 2025Article
- Participants in Transcription-Replication Conflict and Their Role in Formation and Resolution of R-Loops.International journal of molecular sciences · 2025Review
- Review
- APOBEC3A deaminates CTG hairpin loops to promote fragility and instability of expanded CAG/CTG repeats.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- DNA Base Damage Repair Crosstalks with Chromatin Structures to Contract Expanded GAA Repeats in Friedreich's Ataxia.Biomolecules · 2024Article
- Review
- Role of Senataxin in Amyotrophic Lateral Sclerosis.Journal of molecular neuroscience : MN · 2023Review
- Profiling human pathogenic repeat expansion regions by synergistic and multi-level impacts on molecular connections.Human genetics · 2023Article
- RNA-guided DNA base damage repair via DNA polymerase-mediated nick translation.Nucleic acids research · 2023Article
- Article
- Flap Endonuclease 1 Endonucleolytically Processes RNA to Resolve R-Loops through DNA Base Excision Repair.Genes · 2022Article
- The RNA export and RNA decay complexes THO and TRAMP prevent transcription-replication conflicts, DNA breaks, and CAG repeat contractions.PLoS biology · 2022Article
- Review
- Walking a tightrope: The complex balancing act of R-loops in genome stability.Molecular cell · 2022Review
- Article
- Strand-specific effect of Rad26 and TFIIS in rescuing transcriptional arrest by CAG trinucleotide repeat slip-outs.Nucleic acids research · 2021Article
- The Ultimate (Mis)match: When DNA Meets RNA.Cells · 2021Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Trinucleotide repeat (TNR) expansion and deletion are responsible for over 40 neurodegenerative diseases and associated with cancer. TNRs can undergo somatic instability that is mediated by DNA damage and repair and gene transcription. Recent studies have pointed toward a role for R-loops in causing TNR expansion and deletion, and it has been shown that base excision repair (BER) can result in CAG repeat deletion from R-loops in yeast. However, it remains unknown how BER in R-loops can mediate TNR instability. In this study, using biochemical approaches, we examined BER enzymatic activities and their influence on TNR R-loops. We found that AP endonuclease 1 incised an abasic site on the nontemplate strand of a TNR R-loop, creating a double-flap intermediate containing an RNA:DNA hybrid that subsequently inhibited polymerase β (pol β) synthesis of TNRs. This stimulated flap endonuclease 1 (FEN1) cleavage of TNRs engaged in an R-loop. Moreover, we showed that FEN1 also efficiently cleaved the RNA strand, facilitating pol β loop/hairpin bypass synthesis and the resolution of TNR R-loops through BER. Consequently, this resulted in fewer TNRs synthesized by pol β than those removed by FEN1, thereby leading to repeat deletion. Our results indicate that TNR R-loops preferentially lead to repeat deletion during BER by disrupting the balance between the addition and removal of TNRs. Our discoveries open a new avenue for the treatment and prevention of repeat expansion diseases and cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.