TY - JOUR
T1 - Two-tiered enforcement of high-fidelity DNA ligation
AU - Tumbale, Percy P.
AU - Jurkiw, Thomas J.
AU - Schellenberg, Matthew J.
AU - Riccio, Amanda A.
AU - O’Brien, Patrick J.
AU - Williams, R. Scott
N1 - Funding Information:
The research was supported by the US National Institute of Health Intramural Program, US National Institute of Environmental Health Sciences (NIEHS) 1Z01ES102765 (to R.S. W), and the National Institutes of Health Extramural Program, National Institute of General Medical Studies (NIGMS) R01GM130763 (to P.J.O.). T.J.J. was supported in part by a training fellowship from the Cellular Biotechnology Training Program at the University of Michigan (T32GM130763). We thank L. Pedersen of the NIEHS Collaborative crystallography group for data collection support and the Advanced Photon Source (APS) Southeast Regional Collaborative Access Team (SER-CAT) for beamline access. Use of the APS was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31–109-Eng-38. We thank Dr. Tom Kunkel and Dr. Lars Pedersen for comments on the manuscript.
Publisher Copyright:
© 2019, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - DNA ligases catalyze the joining of DNA strands to complete DNA replication, recombination and repair transactions. To protect the integrity of the genome, DNA ligase 1 (LIG1) discriminates against DNA junctions harboring mutagenic 3′-DNA mismatches or oxidative DNA damage, but how such high-fidelity ligation is enforced is unknown. Here, X-ray structures and kinetic analyses of LIG1 complexes with undamaged and oxidatively damaged DNA unveil that LIG1 employs Mg2+-reinforced DNA binding to validate DNA base pairing during the adenylyl transfer and nick-sealing ligation reaction steps. Our results support a model whereby LIG1 fidelity is governed by a high-fidelity (HiFi) interface between LIG1, Mg2+, and the DNA substrate that tunes the enzyme to release pro-mutagenic DNA nicks. In a second tier of protection, LIG1 activity is surveilled by Aprataxin (APTX), which suppresses mutagenic and abortive ligation at sites of oxidative DNA damage.
AB - DNA ligases catalyze the joining of DNA strands to complete DNA replication, recombination and repair transactions. To protect the integrity of the genome, DNA ligase 1 (LIG1) discriminates against DNA junctions harboring mutagenic 3′-DNA mismatches or oxidative DNA damage, but how such high-fidelity ligation is enforced is unknown. Here, X-ray structures and kinetic analyses of LIG1 complexes with undamaged and oxidatively damaged DNA unveil that LIG1 employs Mg2+-reinforced DNA binding to validate DNA base pairing during the adenylyl transfer and nick-sealing ligation reaction steps. Our results support a model whereby LIG1 fidelity is governed by a high-fidelity (HiFi) interface between LIG1, Mg2+, and the DNA substrate that tunes the enzyme to release pro-mutagenic DNA nicks. In a second tier of protection, LIG1 activity is surveilled by Aprataxin (APTX), which suppresses mutagenic and abortive ligation at sites of oxidative DNA damage.
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U2 - 10.1038/s41467-019-13478-7
DO - 10.1038/s41467-019-13478-7
M3 - Article
C2 - 31780661
AN - SCOPUS:85075721577
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5431
ER -