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Peer-reviewedCC BY 4.0Biomolecules

Oxidative RNA Damage Governs Efficiency and Fidelity of RNA-Guided DNA Base Damage Repair

  • Mustapha Olatunji1,2
  • Lucas Bertolami1
  • Jeanpierre Fuente1
  • Dagoberto Grijalva-Flores3
  • Marino J. E. Resendiz3
  • Prem Chapagain1,4,5
  • Yuan Liu1,2,5
5 affiliations
  1. 1Biochemistry Ph.D. Program, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
  2. 2Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
  3. 3Department of Chemistry, University of Colorado Denver, 1151 Arapahoe Street, Denver, CO 80217, USA
  4. 4Department of Physics, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
  5. 5Biomolecular Sciences Institute, Florida International University, 11200 SW 8th Street, Miami, FL 33199, USA
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Abstract

RNAs are essential for gene transcription and protein translation. Yet they also play a crucial role in mediating DNA repair, including RNA-guided DNA base damage repair. However, it is unknown whether RNA integrity can alter DNA repair, modulating genome stability. To address this, we studied the effects of oxidative RNA damage 8-oxoG and an abasic site (AP site) on RNA-guided DNA synthesis and its fidelity by human DNA polymerases on an RNA-DNA hybrid and revealed the underlying molecular mechanisms. We showed that 8-oxoG on an RNA template inhibited pol β DNA synthesis and reduced the fidelity of pol β and pol η by promoting incorrect nucleotide and ribonucleotide incorporation in DNA. We found that an RNA AP site eliminated pol β DNA synthesis and promoted pol η incorporation of dA opposite the AP site. Using AlphaFold3-mediated molecular dynamics simulation, we found that the RNA 8-oxoG and AP site induced unique conformational changes in the RNA-DNA hybrid substrate to disrupt pol β and pol η substrate interaction, leading to RNA-guided nucleotide misincorporation. Our results provide the first insight into the new role of RNA integrity in modulating genome integrity through RNA-guided DNA repair on R-loops.

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Cite

BibTeXRIS
BibTeX
@article{olatunji2026oxidative,
  title = {{Oxidative RNA Damage Governs Efficiency and Fidelity of RNA-Guided DNA Base Damage Repair}},
  author = {Mustapha Olatunji and Lucas Bertolami and Jeanpierre Fuente and Dagoberto Grijalva-Flores and Marino J. E. Resendiz and Prem Chapagain and Yuan Liu},
  journal = {Biomolecules},
  year = {2026},
  month = nov,
  doi = {10.3390/biom16111602},
  url = {https://www.mdpi.com/2218-273X/16/11/1602},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Oxidative RNA Damage Governs Efficiency and Fidelity of RNA-Guided DNA Base Damage Repair
AU  - Mustapha Olatunji
AU  - Lucas Bertolami
AU  - Jeanpierre Fuente
AU  - Dagoberto Grijalva-Flores
AU  - Marino J. E. Resendiz
AU  - Prem Chapagain
AU  - Yuan Liu
PY  - 2026
DA  - 2026/11/03
JO  - Biomolecules
DO  - 10.3390/biom16111602
UR  - https://www.mdpi.com/2218-273X/16/11/1602
AB  - RNAs are essential for gene transcription and protein translation. Yet they also play a crucial role in mediating DNA repair, including RNA-guided DNA base damage repair. However, it is unknown whether RNA integrity can alter DNA repair, modulating genome stability. To address this, we studied the effects of oxidative RNA damage 8-oxoG and an abasic site (AP site) on RNA-guided DNA synthesis and its fidelity by human DNA polymerases on an RNA-DNA hybrid and revealed the underlying molecular mechanisms. We showed that 8-oxoG on an RNA template inhibited pol β DNA synthesis and reduced the fidelity of pol β and pol η by promoting incorrect nucleotide and ribonucleotide incorporation in DNA. We found that an RNA AP site eliminated pol β DNA synthesis and promoted pol η incorporation of dA opposite the AP site. Using AlphaFold3-mediated molecular dynamics simulation, we found that the RNA 8-oxoG and AP site induced unique conformational changes in the RNA-DNA hybrid substrate to disrupt pol β and pol η substrate interaction, leading to RNA-guided nucleotide misincorporation. Our results provide the first insight into the new role of RNA integrity in modulating genome integrity through RNA-guided DNA repair on R-loops.
SN  - 2218-273X
ER  -