Abstract
DNA ligases seal 5'-PO4 and 3'-OH polynucleotide ends via three nucleotidyl transfer steps involving ligase-adenylate and DNA-adenylate intermediates. DNA ligases are essential guardians of genomic integrity, and ligase dysfunction underlies human genetic disease syndromes. Crystal structures of DNA ligases bound to nucleotide and nucleic acid substrates have illuminated how ligase reaction chemistry is catalyzed, how ligases recognize damaged DNA ends, and how protein domain movements and active-site remodeling are used to choreograph the end-joining pathway. Although a shared feature of DNA ligases is their envelopment of the nicked duplex as a C-shaped protein clamp, they accomplish this feat by using remarkably different accessory structural modules and domain topologies. As structural, biochemical, and phylogenetic insights coalesce, we can expect advances on several fronts, including (i) pharmacological targeting of ligases for antibacterial and anticancer therapies and (ii) the discovery and design of new strand-sealing enzymes with unique substrate specificities.
Highlights
The discovery of DNA ligases in 1967 by the Gellert, Lehman, Richardson, and Hurwitz laboratories was a watershed event in molecular biology
DNA ligases are grouped into two families, ATP-dependent ligases and NADϩ-dependent ligases, according to the substrate required for ligase-adenylate formation
The essential elements of the ATP-dependent ligase clade are exemplified by Chlorella virus DNA ligase (ChVLig),2 the smallest eukaryal ligase known [5]
Summary
The discovery of DNA ligases in 1967 by the Gellert, Lehman, Richardson, and Hurwitz laboratories was a watershed event in molecular biology (reviewed in Ref. 1). The crystal structure of E. coli LigA bound to the nicked DNA-adenylate intermediate [12] revealed that LigA encircles the DNA helix as a C-shaped protein clamp (Fig. 3A). The LigA NTase and OB domains are positioned on the DNA circumference to the NTase and OB domains of the ATP-dependent DNA ligases, and they “footprint” similar segments of the DNA strands (supplemental Fig. S3), yet the topology of the LigA clamp is starkly different from that of the clamps formed by ChVLig and HuLig. DNA binding and clamp formation by LigA entail a nearly 180° rotation of the OB domain so that the concave surface of the OB -barrel fits into the minor groove, similar to what is seen or inferred for ChVLig and HuLig. The LigA-DNA interactions immediately flanking the nick induce a local DNA distortion, resulting in adoption of an RNA-like A-form helix, again echoing the findings for the HuLig11⁄7DNA cocrystal
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