Open AccessInterlocking activities of DNA polymerase β in the base excision repair pathway
Author(s) -
Adarsh Kumar,
Andrew J. Reed,
Walter J. Zahurancik,
Sasha M. Daskalova,
Sidney M. Hecht,
Zucai Suo
Publication year - 2022
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2118940119
Subject(s) - base excision repair , dna polymerase , dna repair , dna polymerase beta , dna , deoxyribose , polymerase , microbiology and biotechnology , nucleotide excision repair , dna damage , biology , chemistry , enzyme , biochemistry
Significance Base 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.