Cargando…

RNA-guided DNA base damage repair via DNA polymerase-mediated nick translation

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 unde...

Descripción completa

Detalles Bibliográficos
Autores principales: Tsegay, Pawlos S, Hernandez, Daniela, Qu, Fei, Olatunji, Mustapha, Mamun, Yasir, Chapagain, Prem, Liu, Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9841414/
https://www.ncbi.nlm.nih.gov/pubmed/36533524
http://dx.doi.org/10.1093/nar/gkac1178
Descripción
Sumario: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.