7SUM

Crystal structure of human ligase I with nick duplexes containing cognate A:T

Summary for 7SUM

• Entry DOI: 10.2210/pdb7sum/pdb
• Descriptor: DNA ligase 1, DNA(5'-*GP*CP*TP*GP*AP*TP*GP*CP*GP*TP*A-3'), DNA(5'-P*GP*TP*CP*GP*GP*AP*C-3'), ... (6 entities in total)
• Functional Keywords: ligase-dna complex, ligase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 84378.67

Authors

Tang, Q.,Gulkis, M.,McKenna, R.,Caglayan, M. (deposition date: 2021-11-17, release date: 2022-07-13, Last modification date: 2023-10-18)

Primary citation

Tang, Q.,Gulkis, M.,McKenna, R.,Caglayan, M.
Structures of LIG1 that engage with mutagenic mismatches inserted by pol beta in base excision repair.
Nat Commun, 13:3860-3860, 2022

PubMed Abstract: DNA ligase I (LIG1) catalyzes the ligation of the nick repair intermediate after gap filling by DNA polymerase (pol) β during downstream steps of the base excision repair (BER) pathway. However, how LIG1 discriminates against the mutagenic 3'-mismatches incorporated by polβ at atomic resolution remains undefined. Here, we determine the X-ray structures of LIG1/nick DNA complexes with G:T and A:C mismatches and uncover the ligase strategies that favor or deter the ligation of base substitution errors. Our structures reveal that the LIG1 active site can accommodate a G:T mismatch in the wobble conformation, where an adenylate (AMP) is transferred to the 5'-phosphate of a nick (DNA-AMP), while it stays in the LIG1-AMP intermediate during the initial step of the ligation reaction in the presence of an A:C mismatch at the 3'-strand. Moreover, we show mutagenic ligation and aberrant nick sealing of dG:T and dA:C mismatches, respectively. Finally, we demonstrate that AP-endonuclease 1 (APE1), as a compensatory proofreading enzyme, removes the mismatched bases and interacts with LIG1 at the final BER steps. Our overall findings provide the features of accurate versus mutagenic outcomes coordinated by a multiprotein complex including polβ, LIG1, and APE1 to maintain efficient repair.

PubMed: 35790757
DOI: 10.1038/s41467-022-31585-w

Experimental method

X-RAY DIFFRACTION (2.9 Å)