Summary: Uracil DNA glycosylase superfamily
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DNA glycosylase Edit Wikipedia article
DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.
Glycosylases were first discovered in bacteria, and have since been found in all kingdoms of life. In addition to their role in base excision repair DNA glycosylase enzymes have been implicated in the repression of gene silencing in A. thaliana, N. tabacum and other plants by active demethylation. 5-methylcytosine residues are excised and replaced with unmethylated cytosines allowing access to the chromatin structure of the enzymes and proteins necessary for transcription and subsequent translation.
- 1 Monofunctional vs. bifunctional glycosylases
- 2 Biochemical mechanism
- 3 Types of glycosylases
- 4 History
- 5 Function
- 6 Structure
- 7 Mechanism
- 8 Localisation
- 9 Conservation
- 10 Family
- 11 Pathology
- 12 References
- 13 External links
Monofunctional vs. bifunctional glycosylases
There are two main classes of glycosylases: monofunctional and bifunctional. Monofunctional glycosylases have only glycosylase activity, whereas bifunctional glycosylases also possess AP lyase activity that permits them to cut the phosphodiester bond of DNA, creating a single-strand break without the need for an AP endonuclease. β-Elimination of an AP site by a glycosylase-lyase yields a 3' α,β-unsaturated aldehyde adjacent to a 5' phosphate, which differs from the AP endonuclease cleavage product. Some glycosylase-lyases can further perform δ-elimination, which converts the 3' aldehyde to a 3' phosphate.
The first crystal structure of a DNA glycosylase was obtained for E. coli Nth. This structure revealed that the enzyme flips the damaged base out of the double helix into an active site pocket in order to excise it. Other glycosylases have since been found to follow the same general paradigm, including human UNG pictured below. To cleave the N-glycosidic bond, monofunctional glycosylases use an activated water molecule to attack carbon 1 of the substrate. Bifunctional glycosylases, instead, use an amine residue as a nucleophile to attack the same carbon, going through a Schiff base intermediate.
Types of glycosylases
Crystal structures of many glycosylases have been solved. Based on structural similarity, glycosylases are grouped into four superfamilies. The UDG and AAG families contain small, compact glycosylases, whereas the MutM/Fpg and HhH-GPD families comprise larger enzymes with multiple domains.
A wide variety of glycosylases have evolved to recognize different damaged bases. The table below summarizes the properties of known glycosylases in commonly studied model organisms.
|E. coli||Yeast (S. cerevisiae)||Human||Type||Substrates|
|Nth||Ntg1||hNTH1||bifunctional||Tg, hoU, hoC, urea, FapyG|
|Nei||Not present||hNEIL1||bifunctional||Tg, hoU, hoC, urea, FapyG, FapyA|
|hNEIL2||AP site, hoU|
|Not present||Not present||hSMUG1||monofunctional||U, hoU, hmU, fU|
|Not present||Not present||TDG||monofunctional||T:G mispair|
|Not present||Not present||MBD4||monofunctional||T:G mispair|
DNA glycosylases can be grouped into the following categories based on their substrate(s):
Uracil DNA glycosylases
In molecular biology, the protein family, Uracil-DNA glycosylase (UDG) is an enzyme that reverts mutations in DNA. The most common mutation is the deamination of cytosine to uracil. UDG repairs these mutations. UDG is crucial in DNA repair, without it these mutations may lead to cancer.
This entry represents various uracil-DNA glycosylases and related DNA glycosylases (EC), such as uracil-DNA glycosylase, thermophilic uracil-DNA glycosylase, G:T/U mismatch-specific DNA glycosylase (Mug), and single-strand selective monofunctional uracil-DNA glycosylase (SMUG1).
Uracil DNA glycosylases remove uracil from DNA, which can arise either by spontaneous deamination of cytosine or by the misincorporation of dU opposite dA during DNA replication. The prototypical member of this family is E. coli UDG, which was among the first glycosylases discovered. Four different uracil-DNA glycosylase activities have been identified in mammalian cells, including UNG, SMUG1, TDG, and MBD4. They vary in substrate specificity and subcellular localization. SMUG1 prefers single-stranded DNA as substrate, but also removes U from double-stranded DNA. In addition to unmodified uracil, SMUG1 can excise 5-hydroxyuracil, 5-hydroxymethyluracil and 5-formyluracil bearing an oxidized group at ring C5. TDG and MBD4 are strictly specific for double-stranded DNA. TDG can remove thymine glycol when present opposite guanine, as well as derivatives of U with modifications at carbon 5. Current evidence suggests that, in human cells, TDG and SMUG1 are the major enzymes responsible for the repair of the U:G mispairs caused by spontaneous cytosine deamination, whereas uracil arising in DNA through dU misincorporation is mainly dealt with by UNG. MBD4 is thought to correct T:G mismatches that arise from deamination of 5-methylcytosine to thymine in CpG sites. MBD4 mutant mice develop normally and do not show increased cancer susceptibility or reduced survival. But they acquire more C T mutations at CpG sequences in epithelial cells of the small intestine.
The structure of human UNG in complex with DNA revealed that, like other glycosylases, it flips the target nucleotide out of the double helix and into the active site pocket. UDG undergoes a conformational change from an ‘‘open’’ unbound state to a ‘‘closed’’ DNA-bound state.
epstein-barr virus uracil-dna glycosylase in complex with ugi from pbs-2
Lindahl was the first to observe repair of uracil in DNA. UDG was purified from Escherichia coli, and this hydrolysed the N-glycosidic bond connecting the base to the deoxyribose sugar of the DNA backbone.
The function of UDG is to remove mutations in DNA, more specifically removing uracil.
These proteins have a 3-layer alpha/beta/alpha structure. The polypeptide topology of UDG is that of a classic alpha/beta protein. The structure consists primarily of a central, four-stranded, all parallel beta sheet surrounded on either side by a total of eight alpha helices and is termed a parallel doubly wound beta sheet.
Uracil-DNA glycosylases are DNA repair enzymes that excise uracil residues from DNA by cleaving the N-glycosydic bond, initiating the base excision repair pathway. Uracil in DNA can arise either through the deamination of cytosine to form mutagenic U:G mispairs, or through the incorporation of dUMP by DNA polymerase to form U:A pairs. These aberrant uracil residues are genotoxic.
The sequence of uracil-DNA glycosylase is extremely well conserved  in bacteria and eukaryotes as well as in herpes viruses. More distantly related uracil-DNA glycosylases are also found in poxviruses. The N-terminal 77 amino acids of UNG1 seem to be required for mitochondrial localization, but the presence of a mitochondrial transit peptide has not been directly demonstrated. The most N-terminal conserved region contains an aspartic acid residue which has been proposed, based on X-ray structures  to act as a general base in the catalytic mechanism.
Glycosylases of oxidized bases
A variety of glycosylases have evolved to recognize oxidized bases, which are commonly formed by reactive oxygen species generated during cellular metabolism. The most abundant lesions formed at guanine residues are 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG) and 8-oxoguanine. Due to mispairing with adenine during replication, 8-oxoG is highly mutagenic, resulting in G to T transversions. Repair of this lesion is initiated by the bifunctional DNA glycosylase OGG1, which recognizes 8-oxoG paired with C. hOGG1 is a bifunctional glycosylase that belongs to the helix-hairpin-helix (HhH) family. MYH recognizes adenine mispaired with 8-oxoG but excises the A, leaving the 8-oxoG intact. OGG1 knockout mice do not show an increased tumor incidence, but accumulate 8-oxoG in the liver as they age. A similar phenotype is observed with the inactivation of MYH, but simultaneous inactivation of both MYH and OGG1 causes 8-oxoG accumulation in multiple tissues including lung and small intestine. In humans, mutations in MYH are associated with increased risk of developing colon polyps and colon cancer. In addition to OGG1 and MYH, human cells contain three additional DNA glycosylases, NEIL1, NEIL2, and NEIL3. These are homologous to bacterial Nei, and their presence likely explains the mild phenotypes of the OGG1 and MYH knockout mice.
Glycosylases of alkylated bases
This group includes E. coli AlkA and related proteins in higher eukaryotes. These glycosylases are monofunctional and recognize methylated bases, such as 3-methyladenine.
- DNA glycosylases involved in base excision repair (BER)
- Aguis, F.; Kapoor, A. and Zhu. J-K. (2006). "Role of the Arabidopsis DNA glycosylase/lyase ROS1 in active DNA demethylation". Proc. Natl. Acad. Sci. U.S.A. 103 (31): 11796–11801. doi:10.1073/pnas.0603563103.
- Choi, C-S.; Sano, H. (2007). "Identification of tobacco genes encoding proteins possessing removal activity of 5-methylcytosines from intact tobacco DNA". Plant Biotechnology 24: 339–344. doi:10.5511/plantbiotechnology.24.339.
- Fromme JC, Banerjee A, Verdine GL (February 2004). "DNA glycosylase recognition and catalysis". Current Opinion in Structural Biology 14 (1): 43–9. doi:10.1016/j.sbi.2004.01.003. PMID 15102448.
- Kuo CF, McRee DE, Fisher CL, O'Handley SF, Cunningham RP, Tainer JA (October 1992). "Atomic structure of the DNA repair [4Fe-4S] enzyme endonuclease III". Science 258 (5081): 434–40. doi:10.1126/science.1411536. PMID 1411536.
- Ide H, Kotera M (April 2004). "Human DNA glycosylases involved in the repair of oxidatively damaged DNA". Biol. Pharm. Bull. 27 (4): 480–5. doi:10.1248/bpb.27.480. PMID 15056851.
- Alseth I, Osman F, Korvald H, et al. (2005). "Biochemical characterization and DNA repair pathway interactions of Mag1-mediated base excision repair in Schizosaccharomyces pombe". Nucleic Acids Res. 33 (3): 1123–31. doi:10.1093/nar/gki259. PMC 549418. PMID 15722486.
- Pearl LH (2000). "Structure and function in the uracil-DNA glycosylase superfamily.". Mutat Res 460 (3-4): 165–81. doi:10.1016/S0921-8777(00)00025-2. PMID 10946227.
- Mol CD, Arvai AS, Slupphaug G, Kavli B, Alseth I, Krokan HE, Tainer JA (March 1995). "Crystal structure and mutational analysis of human uracil-DNA glycosylase: structural basis for specificity and catalysis". Cell 80 (6): 869–78. doi:10.1016/0092-8674(95)90290-2. PMID 7697717.
- Sandigursky M, Franklin WA (May 1999). "Thermostable uracil-DNA glycosylase from Thermotoga maritima a member of a novel class of DNA repair enzymes". Curr. Biol. 9 (10): 531–4. doi:10.1016/S0960-9822(99)80237-1. PMID 10339434.
- Barrett TE, Savva R, Panayotou G, Barlow T, Brown T, Jiricny J, Pearl LH (January 1998). "Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions". Cell 92 (1): 117–29. doi:10.1016/S0092-8674(00)80904-6. PMID 9489705.
- Buckley B, Ehrenfeld E (October 1987). "The cap-binding protein complex in uninfected and poliovirus-infected HeLa cells". J. Biol. Chem. 262 (28): 13599–606. PMID 2820976.
- Matsubara M, Tanaka T, Terato H, Ohmae E, Izumi S, Katayanagi K, Ide H (2004). "Mutational analysis of the damage-recognition and catalytic mechanism of human SMUG1 DNA glycosylase". Nucleic Acids Res 32 (17): 5291–5302. doi:10.1093/nar/gkh859.
- Wu P, Qiu C, Sohail A, Zhang X, Bhagwat, AS, Xiaodong C. (2003). Mismatch Repair in Methylated DNA. STRUCTURE AND ACTIVITY OF THE MISMATCH-SPECIFIC THYMINE GLYCOSYLASE DOMAIN OF METHYL-CpG-BINDING PROTEIN MBD4. 5285-5291.
- Wong E, Yang K, Kuraguchi M, Werling U, Avdievich E, Fan K, Fazzari M, Jin B, Brown M.C et al. (1995). "Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation". PNAS 99 (23): 14937–14942.
- Mol CD, Arvai AS, Slupphaug G, Kavli B, Alseth I, Krokan HE, Tainer JA (1995). "Crystal structure and mutational analysis of human uracil-DNA glycosylase". Cell 80 (6): 869–878. doi:10.1016/0092-8674(95)90290-2. PMID 7697717.
- Slupphaug G, Mol CD, Kavli B, Arvai AS, Krokan HE, Tainer JA. (1996). A nucleotide-flipping mechanism from the structure of human uracil–DNA glycosylase bound to DNA. 384: 87-92.
- Kavli B, Otterlei M, Slupphaug G, Krokan HE (April 2007). "Uracil in DNA--general mutagen, but normal intermediate in acquired immunity". DNA Repair (Amst.) 6 (4): 505–16. doi:10.1016/j.dnarep.2006.10.014. PMID 17116429.
- Hagen L, PeÃ±a-Diaz J, Kavli B, Otterlei M, Slupphaug G, Krokan HE (August 2006). "Genomic uracil and human disease". Exp. Cell Res. 312 (14): 2666–72. doi:10.1016/j.yexcr.2006.06.015. PMID 16860315.
- Slupphaug G, Markussen FH, Olsen LC, Aasland R, Aarsaether N, Bakke O, Krokan HE, Helland DE (June 1993). "Nuclear and mitochondrial forms of human uracil-DNA glycosylase are encoded by the same gene". Nucleic Acids Res. 21 (11): 2579–84. doi:10.1093/nar/21.11.2579. PMC 309584. PMID 8332455.
- Olsen LC, Aasland R, Wittwer CU, Krokan HE, Helland DE (October 1989). "Molecular cloning of human uracil-DNA glycosylase, a highly conserved DNA repair enzyme". EMBO J. 8 (10): 3121–5. PMC 401392. PMID 2555154.
- Upton C, Stuart DT, McFadden G (May 1993). "Identification of a poxvirus gene encoding a uracil DNA glycosylase". Proc. Natl. Acad. Sci. U.S.A. 90 (10): 4518–22. doi:10.1073/pnas.90.10.4518. PMC 46543. PMID 8389453.
- Savva R, McAuley-Hecht K, Brown T, Pearl L (February 1995). "The structural basis of specific base-excision repair by uracil-DNA glycosylase". Nature 373 (6514): 487–93. doi:10.1038/373487a0. PMID 7845459.
- Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe A, Seeberg E, Lindahl T, Barnes D. E. et al. (1999). "Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage". PNAS 96 (23): 13300–13305. doi:10.1073/pnas.96.23.13300.
- Russo M.T, De , Degan P, Parlanti E, Dogliotti E Barnes D.E, Lindahl T, Yang H, Miller J. H, Bignami M. et al. (2004). "Accumulation of the Oxidative Base Lesion 8-Hydroxyguanine in DNA of Tumor-Prone Mice Defective in Both the Myh and Ogg1 DNA Glycosylases". Cancer Res 64 (13): 4411–4414. doi:10.1158/0008-5472.can-04-0355.
- Structure-function studies of an unusual 3-methyladenine DNA glycosylase II (AlkA) from Deinococcus radiodurans. 2012
- Osorio, A; Milne, R. L.; Kuchenbaecker, K; Vaclová, T; Pita, G; Alonso, R; Peterlongo, P; Blanco, I; de la Hoya, M; Duran, M; Díez, O; Ramón y Cajal, T; Konstantopoulou, I; Martínez-Bouzas, C; Andrés Conejero, R; Soucy, P; McGuffog, L; Barrowdale, D; Lee, A; Swe-Brca; Arver, B; Rantala, J; Loman, N; Ehrencrona, H; Olopade, O. I.; Beattie, M. S.; Domchek, S. M.; Nathanson, K; Rebbeck, T. R. et al. (2014). "DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers". PLoS Genetics 10 (4): e1004256. doi:10.1371/journal.pgen.1004256. PMID 24698998.
Uracil DNA glycosylase superfamily Provide feedback
No Pfam abstract.
Barrett TE, Savva R, Panayotou G, Barlow T, Brown T, Jiricny J, Pearl LH; , Cell 1998;92:117-129.: Crystal structure of a G:T/U mismatch-specific DNA glycosylase: mismatch recognition by complementary-strand interactions. PUBMED:9489705 EPMC:9489705
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR005122
This entry represents various uracil-DNA glycosylases and related DNA glycosylases (EC), such as uracil-DNA glycosylase [PUBMED:7697717], thermophilic uracil-DNA glycosylase [PUBMED:10339434], G:T/U mismatch-specific DNA glycosylase (Mug) [PUBMED:9489705], and single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) [PUBMED:2820976]. These proteins have a 3-layer alpha/beta/alpha structure. Uracil-DNA glycosylases are DNA repair enzymes that excise uracil residues from DNA by cleaving the N-glycosylic bond, initiating the base excision repair pathway. Uracil in DNA can arise either through the deamination of cytosine to form mutagenic U:G mispairs, or through the incorporation of dUMP by DNA polymerase to form U:A pairs [PUBMED:17116429]. These aberrant uracil residues are genotoxic [PUBMED:16860315]. The sequence of uracil-DNA glycosylase is extremely well conserved [PUBMED:2555154] in bacteria and eukaryotes as well as in herpes viruses. More distantly related uracil-DNA glycosylases are also found in poxviruses [PUBMED:8389453]. In eukaryotic cells, UNG activity is found in both the nucleus and the mitochondria. Human UNG1 protein is transported to both the mitochondria and the nucleus [PUBMED:8332455]. The N-terminal 77 amino acids of UNG1 seem to be required for mitochondrial localization, but the presence of a mitochondrial transit peptide has not been directly demonstrated. The most N-terminal conserved region contains an aspartic acid residue which has been proposed, based on X-ray structures [PUBMED:7845459] to act as a general base in the catalytic mechanism.
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Curation and family details
|Seed source:||Aravind L|
|Number in seed:||164|
|Number in full:||10115|
|Average length of the domain:||160.00 aa|
|Average identity of full alignment:||22 %|
|Average coverage of the sequence by the domain:||68.49 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the UDG domain has been found. There are 114 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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