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Structures of LIG1 engaging with mutagenic mismatches inserted by polβ in base excision repair
Author(s) -
Caglayan Melike
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.0r459
Subject(s) - dna ligase , dna mismatch repair , base excision repair , ligation , endonuclease , ap site , microbiology and biotechnology , dna repair , dna polymerase , dna , base pair , proofreading , biology , chemistry , genetics
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 covalent 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 final BER steps where a multi‐protein complex including polβ, LIG1, and APE1 can maintain accurate repair.