title: Structure and function in the uracil-DNA glycosylase superfamily.
abstract: Deamination of cytosine to uracil is one of the major pro-mutagenic events in DNA, causing G:C-->A:T transition mutations if not repaired before replication. Repair of uracil-DNA is achieved in a base-excision pathway initiated by a uracil-DNA glycosylase (UDG) enzyme of which four families have so far been identified. Family-1 enzymes are active against uracil in ssDNA and dsDNA, and recognise uracil explicitly in an extrahelical conformation via a combination of protein and bound-water interactions. Extrahelical recognition requires an efficient process of substrate location by 'base-sampling' probably by hopping or gliding along the DNA. Family-2 enzymes are mismatch specific and explicitly recognise the widowed guanine on the complementary strand rather than the extrahelical scissile pyrimidine. This allows a broader specificity so that some Family-2 enzymes can excise uracil and 3, N(4)-ethenocytosine from mismatches with guanine. Although structures are not yet available for Family-3 (SMUG) and Family-4 enzymes, sequence analysis suggests similar overall folds, and identifies common active site motifs but with a surprising lack of conservation of catalytic residues between members of the super-family.
authors.affiliation: Section of Structural Biology and CRC DNA Repair Enzyme Group, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, SW3 6JB, London, UK. laurence@icr.ac.uk
authors.forename: L H
authors.initials: LH
authors.lastname: Pearl
mesh_terms: D000595:Amino Acid Sequence; D019843:Archaeal Proteins / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry; D020029:Base Pairing; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases; D004260:DNA Repair; D003641:Deamination; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D018259:Herpesvirus 1, Human / Q000201:enzymology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D009699:N-Glycosyl Hydrolases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000502:physiology; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020124:Thermotoga maritima / Q000201:enzymology; D044502:Thymine DNA Glycosylase; D014498:Uracil / Q000737:chemistry; D051981:Uracil-DNA Glycosidase; D014764:Viral Proteins / Q000737:chemistry
chemical_list: C018289:3,N(4)-ethenocytosine; D019843:Archaeal Proteins; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D014764:Viral Proteins; D014498:Uracil; D003596:Cytosine; D004247:DNA; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D044502:Thymine DNA Glycosylase; D051981:Uracil-DNA Glycosidase; C412878:double-strand uracil-DNA glycosylase, E coli; C113921:mismatch-specific thymine uracil-DNA glycosylase