RNA-guided DNA base damage repair via DNA polymerase-mediated nick translation. Issue 1 (19th December 2022)

• Record Type: Journal Article
• Authors: Tsegay, Pawlos S; Hernandez, Daniela; Qu, Fei; Olatunji, Mustapha; Mamun, Yasir; Chapagain, Prem; Liu, Yuan
• Is Part Of: Nucleic acids research. Volume 51:Issue 1(2023)
• Page Start: 166
• Page End: 181
• Publication Date: 2022-12-19
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkac1178
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: DNA repair is mediated by DNA synthesis guided by a DNA template. Recent studies have shown that DNA repair can also be accomplished by RNA-guided DNA synthesis. However, it remains unknown how RNA can guide DNA synthesis to repair DNA damage. In this study, we revealed the molecular mechanisms underlying RNA-guided DNA synthesis and base damage repair mediated by human repair DNA polymerases. We showed that pol β, pol κ, and pol ι predominantly synthesized one nucleotide, and pol η, pol ν, and pol θ synthesized multi-nucleotides during RNA-guided DNA base damage repair. The steady-state kinetics showed that pol η exhibited more efficient RNA-guided DNA synthesis than pol β. Using molecular dynamics simulation, we further revealed dynamic conformational changes of pol β and pol η and their structural basis to accommodate the RNA template and misoriented triphosphates of an incoming nucleotide. We demonstrated that RNA-guided base damage repair could be accomplished by the RNA-guided DNA strand-displacement synthesis and nick translation leading to nick ligation in a double-strand DNA region. Our study revealed a novel RNA-guided base damage repair pathway during transcription and DNA replication.