Interlocking activities of DNA polymerase β in the base excision repair pathway

Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2118940119. doi: 10.1073/pnas.2118940119. Epub 2022 Mar 1.


SignificanceBase excision repair (BER) is one of the major DNA repair pathways used to fix a myriad of cellular DNA lesions. The enzymes involved in BER, including DNA polymerase β (Polβ), have been identified and characterized, but how they act together to efficiently perform BER has not been fully understood. Through gel electrophoresis, mass spectrometry, and kinetic analysis, we discovered that the two enzymatic activities of Polβ can be interlocked, rather than functioning independently from each other, when processing DNA intermediates formed in BER. The finding prompted us to hypothesize a modified BER pathway. Through conventional and time-resolved X-ray crystallography, we solved 11 high-resolution crystal structures of cross-linked Polβ complexes and proposed a detailed chemical mechanism for Polβ's 5'-deoxyribose-5-phosphate lyase activity.

Keywords: DNA base excision repair pathway; DNA polymerase β; Schiff base formation; dRP lyase chemical mechanism; β-elimination.

MeSH terms

  • Crystallography, X-Ray
  • DNA / metabolism
  • DNA Damage*
  • DNA Polymerase beta / chemistry
  • DNA Polymerase beta / metabolism*
  • DNA Repair*
  • Electrophoresis, Polyacrylamide Gel
  • Kinetics
  • Mass Spectrometry / methods
  • Protein Conformation
  • Schiff Bases / chemistry
  • Substrate Specificity


  • Schiff Bases
  • DNA
  • DNA Polymerase beta