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R-loops promote trinucleotide repeat deletion through DNA base excision repair enzymatic activities

Trinucleotide repeat (TNR) expansion and deletion are responsible for over 40 neurodegenerative diseases and associated with cancer. TNR can undergo somatic instability that is mediated by DNA damage and repair, and gene transcription. Recent studies have pointed towards a role for R-loops in causing TNR expansion and deletion, and it's been shown that base excision repair (BER) can result in CAG repeat deletions from R-loops in yeast. However, it remains unknown how BER in R-loops can mediate TNR instability. In this study, using biochemical approaches, the authors examined BER enzymatic activities and their influence on TNR-R-loops. This study found that AP endonuclease 1 incised an abasic site on the non-template strand of a TNR R-loop, creating a double-flap intermediate containing an RNA-DNA hybrid that subsequently inhibited pol β DNA synthesis of TNRs. This stimulated flap endonuclease 1 (FEN1) cleavage of TNRs engaged in an R-loop. Moreover, the authors 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. These results indicate that TNR R-loops preferentially lead to repeat deletion during BER by disrupting the balance between the addition and removal of TNRs. These discoveries open a new avenue for the treatments and prevention of repeat expansion diseases and cancer.

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