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Structures of LIG1 engaging with mutagenic mismatches inserted by polβ in base excision repair

Qun Tang, Robert McKenna, Melike Çağlayan
doi: https://doi.org/10.1101/2022.01.14.473406
Qun Tang
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA
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Robert McKenna
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA
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Melike Çağlayan
Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA
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  • For correspondence: caglayanm@ufl.edu
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ABSTRACT

DNA ligase I (LIG1) catalyzes final ligation step following DNA polymerase (pol) β gap filling and an incorrect nucleotide insertion by polβ creates a nick repair intermediate with mismatched end at the downstream steps of base excision repair (BER) pathway. Yet, how LIG1 discriminates against the mutagenic 3′-mismatches at atomic resolution remains undefined. Here, we determined X-ray structures of LIG1/nick DNA complexes with G:T and A:C mismatches and uncovered the ligase strategies that favor or deter ligation of base substitution errors. Our structures revealed that LIG1 active site can accommodate G:T mismatch in a similar conformation with A:T base pairing, while it stays in the LIG1-adenylate intermediate during initial step of ligation reaction in the presence of A:C mismatch at 3′-strand. Moreover, we showed mutagenic ligation and aberrant nick sealing of the nick DNA substrates with 3′-preinserted dG:T and dA:C mismatches, respectively. Finally, we demonstrated that AP-Endonuclease 1 (APE1), as a compensatory proofreading enzyme, interacts and coordinates with LIG1 during mismatch removal and DNA ligation. Our overall findings and ligase/nick DNA structures provide the features of accurate versus mutagenic outcomes at the final BER steps where a multi-protein complex including polβ, LIG1, and APE1 can maintain accurate repair.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 14, 2022.
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Structures of LIG1 engaging with mutagenic mismatches inserted by polβ in base excision repair
Qun Tang, Robert McKenna, Melike Çağlayan
bioRxiv 2022.01.14.473406; doi: https://doi.org/10.1101/2022.01.14.473406
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Structures of LIG1 engaging with mutagenic mismatches inserted by polβ in base excision repair
Qun Tang, Robert McKenna, Melike Çağlayan
bioRxiv 2022.01.14.473406; doi: https://doi.org/10.1101/2022.01.14.473406

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