Zinc finger, DNA glycosylase/AP lyase-type (Znf_DNA_glyclase/AP_lyase)
Type: Domain

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

This entry represents DNA glycosylase/AP lyase enzymes that are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. These enzymes are primarily from bacteria, and have both DNA glycosylase activity (

) and AP lyase activity (

). Examples include formamidopyrimidine-DNA glycosylases (Fpg; MutM) and endonuclease VIII (Nei). These enzymes contain a zinc finger domain that is important for DNA-binding.

Formamidopyrimidine-DNA glycosylases (Fpg, MutM) is a trifunctional DNA base excision repair enzyme that removes a wide range of oxidation-damaged bases (N-glycosylase activity;

) and cleaves both the 3'- and 5'-phosphodiester bonds of the resulting apurinic/apyrimidinic site (AP lyase activity;

). Fpg has a preference for oxidised purines, excising oxidized purine bases such as 7,8-dihydro-8-oxoguanine (8-oxoG). ITs AP (apurinic/apyrimidinic) lyase activity introduces nicks in the DNA strand, cleaving the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Fpg is a monomer composed of 2 domains connected by a flexible hinge . The two DNA-binding motifs (a zinc finger and the helix-two-turns-helix motifs) suggest that the oxidized base is flipped out from double-stranded DNA in the binding mode and excised by a catalytic mechanism similar to that of bifunctional base excision repair enzymes . Fpg binds one ion of zinc at the C terminus, which contains four conserved and essential cysteines .

Endonuclease VIII (Nei) has the same enzyme activities as Fpg above (

,

), but with a preference for oxidized pyrimidines, such as thymine glycol, 5,6-dihydrouracil and 5,6-dihydrothymine . Three human homologues of Escherichia coli Nei have been identified, called Nei-like (NEIL) enzyme. NEIL2 (Nei-like-2) shares structural features and reaction mechanism with E. coli Nei (and Fpg), but it contains a C4-type zinc finger in place of the CHCC-type found in Nei and Fpg . By contrast, the structure of NEIL1 exhibits the same overall fold as E. coli Nei; however, the β-hairpin zinc finger found in other Fpg/Nei family members is replaced by a structural motif composed of two antiparallel β-strands that mimics a zinc finger but lacks the loops that harbour the zinc-binding residues and, therefore, does not coordinate zinc . This entry identifies the zinc finger in NEIL2, but not the "zincless finger" in NEIL1.