2. Academic Validation
  3. Interlocking activities of DNA polymerase β in the base excision repair pathway

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.
Adarsh Kumar 1,  Andrew J Reed 2,  Walter J Zahurancik 2,  Sasha M Daskalova 3,  Sidney M Hecht 3,  Zucai Suo 1 2
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306.
  • 2 The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210.
  • 3 Biodesign Center for BioEnergetics and School of Molecular Sciences, Arizona State University, Tempe, AZ 85287.
PMID: 35238634 DOI: 10.1073/pnas.2118940119
Abstract

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.

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