7KR4

Human DNA Ligase 1(E346A/E592A) Bound to a nicked DNA substrate control duplex

Summary for 7KR4

• Entry DOI: 10.2210/pdb7kr4/pdb
• Descriptor: DNA ligase 1, DNA (5'-D(*AP*AP*TP*GP*TP*CP*TP*GP*CP*CP*C)-3'), DNA (5'-D(P*AP*TP*TP*CP*TP*GP*C)-3'), ... (7 entities in total)
• Functional Keywords: dna ligase, dna replication, dna repair, replication fidelity, ligase, ligase-dna complex, ligase/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 83486.84

Authors

Tumbale, P.P.,Williams, R.S. (deposition date: 2020-11-18, release date: 2021-02-03, Last modification date: 2023-10-18)

Primary citation

Williams, J.S.,Tumbale, P.P.,Arana, M.E.,Rana, J.A.,Williams, R.S.,Kunkel, T.A.
High-fidelity DNA ligation enforces accurate Okazaki fragment maturation during DNA replication.
Nat Commun, 12:482-482, 2021

PubMed Abstract: DNA ligase 1 (LIG1, Cdc9 in yeast) finalizes eukaryotic nuclear DNA replication by sealing Okazaki fragments using DNA end-joining reactions that strongly discriminate against incorrectly paired DNA substrates. Whether intrinsic ligation fidelity contributes to the accuracy of replication of the nuclear genome is unknown. Here, we show that an engineered low-fidelity LIG1 variant confers a novel mutator phenotype in yeast typified by the accumulation of single base insertion mutations in homonucleotide runs. The rate at which these additions are generated increases upon concomitant inactivation of DNA mismatch repair, or by inactivation of the Fen1 Okazaki fragment maturation (OFM) nuclease. Biochemical and structural data establish that LIG1 normally avoids erroneous ligation of DNA polymerase slippage products, and this protection is compromised by mutation of a LIG1 high-fidelity metal binding site. Collectively, our data indicate that high-fidelity DNA ligation is required to prevent insertion mutations, and that this may be particularly critical following strand displacement synthesis during the completion of OFM.

PubMed: 33473124
DOI: 10.1038/s41467-020-20800-1

Experimental method

X-RAY DIFFRACTION (2.2 Å)