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 Epigenetic deficiencies in cancers
- 13 References
- 14 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||B. cereus||Yeast (S. cerevisiae)||Human||Type||Substrates|
|AlkA||AlkE||Mag1||MPG (N-methylpurine DNA glycosylase)||monofunctional||3-meA(3-alkyladenine), hypoxanthine|
|Fpg||Ogg1||hOGG1||bifunctional||8-oxoG (8-Oxoguanine), FapyG|
|Nth||Ntg1||hNTH1||bifunctional||Tg, hoU, hoC, urea, FapyG(2,6-diamino-4-hydroxy-5-formamidopyrimidine)|
|Nei||Not present||hNEIL1||bifunctional||Tg, hoU, hoC, urea, FapyG, FapyA(4,6-diamino-5-formamidopyrimidine)|
|hNEIL2||AP site, hoU|
|Not present||Not present||hSMUG1||monofunctional||U, hoU(5-hydroxyuracil), hmU(5-hydroxymethyluracil), fU(5-formyluracil)|
|Not present||Not present||TDG||monofunctional||T:G mispair|
|Not present||Not present||MBD4||monofunctional||T:G mispair|
|AlkC||AlkC||Not present||Not present||monofunctional||Alkylpurine|
|AlkD||AlkD||Not present||Not present||monofunctional||Alkylpurine|
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) may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.
Epigenetic deficiencies in cancers
Epigenetic alterations (epimutations) in DNA glycosylase genes have only recently begun to be evaluated in a few cancers, compared to the numerous previous studies of epimutations in genes acting in other DNA repair pathways (such as MLH1 in mismatch repair and MGMT in direct reversal). Two examples of epimutations in DNA glycosylase genes that occur in cancers are summarized below.
MBD4 (methyl-CpG-binding domain protein 4) is a glycosylase employed in an initial step of base excision repair. MBD4 protein binds preferentially to fully methylated CpG sites. These altered bases arise from the frequent hydrolysis of cytosine to uracil (see image) and hydrolysis of 5-methylcytosine to thymine, producing G:U and G:T base pairs. If the improper uracils or thymines in these base pairs are not removed before DNA replication, they will cause transition mutations. MBD4 specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites. This is an important repair function since about 1/3 of all intragenic single base pair mutations in human cancers occur in CpG dinucleotides and are the result of G:C to A:T transitions. These transitions comprise the most frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites. Thus, a decrease in expression of MBD4 could cause an increase in carcinogenic mutations.
A majority of histologically normal fields surrounding neoplastic growths (adenomas and colon cancers) in the colon also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue from individuals who never had a colonic neoplasm. This finding suggests that epigenetic silencing of MBD4 is an early step in colorectal carcinogenesis.
In a Chinese population that was evaluated, the MBD4 Glu346Lys polymorphism was associated with about a 50% reduced risk of cervical cancer, suggesting that alterations in MBD4 is important in this cancer.
Nei-like (NEIL) 1 is a DNA glycosylase of the Nei family (which also contains NEIL2 and NEIL3). NEIL1 is a component of the DNA replication complex needed for surveillance of oxidized bases before replication, and appears to act as a “cowcatcher” to slow replication until NEIL1 can act as a glycosylase and remove the oxidatively damaged base.
NEIL1 protein recognizes (targets) and removes certain oxidatively-damaged bases and then incises the abasic site via β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines, formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine glycol. The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing lesions from single-stranded DNA as well as from bubble and forked DNA structures. A deficiency in NEIL1 causes increased mutagenesis at the site of an 8-oxo-Gua:C pair, with most mutations being G:C to T:A transversions.
A study in 2004 found that 46% of primary gastric cancers had reduced expression of NEIL1 mRNA, though the mechanism of reduction was not known. This study also found that 4% of gastric cancers had mutations in the NEIL1 gene. The authors suggested that low NEIL1 activity arising from reduced expression and/or mutation of the NEIL1 gene was often involved in gastric carcinogenesis.
A screen of 145 DNA repair genes for aberrant promoter methylation was performed on head and neck squamous cell carcinoma (HNSCC) tissues from 20 patients and from head and neck mucosa samples from 5 non-cancer patients. This screen showed that the NEIL1 gene had substantially increased hypermethylation, and of the 145 DNA repair genes evaluated, NEIL1 had the most significantly different frequency of methylation. Furthermore, the hypermethylation corresponded to a decrease in NEIL1 mRNA expression. Further work with 135 tumor and 38 normal tissues also showed that 71% of HNSCC tissue samples had elevated NEIL1 promoter methylation.
When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors, 42% were hypermethylated in the NEIL1 promoter region. This was the most frequent DNA repair abnormality found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be hypermethylated in their promoter regions in colorectal cancer.
- Lindahl, T. (1986). "DNA Glycosylases in DNA Repair". Mechanisms of DNA Damage and Repair: 335–340. doi:10.1007/978-1-4615-9462-8_36. ISBN 978-1-4615-9464-2.
- Aguis, F.; Kapoor, A; 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. PMC .
- 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 . 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. PMC . PMID 15466595.
- 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. doi:10.1073/pnas.232579299. PMC . PMID 12417741.
- 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; Peña-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 . 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 . 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 . 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. PMC . PMID 10557315.
- 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. PMID 15231648.
- Moe E, Hall DR, Leiros I, Monsen VT, Timmins J, McSweeney S. "Structure-function studies of an unusual 3-methyladenine DNA glycosylase II (AlkA) from Deinococcus radiodurans". Acta Crystallogr D. 68: 703–12. doi:10.1107/S090744491200947X. PMID 22683793.
- 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. PMC . PMID 24698998.
- Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-2209-8, InTech, Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer
- Walavalkar, Ninad (2014). "Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches". Nucleic Acids Research. 42 (17): 11218-11232. doi:10.1093/nar/gku782.
- Bellacosa A, Drohat AC (Aug 2015). "Role of base excision repair in maintaining the genetic and epigenetic integrity of CpG sites". DNA Repair. 32: 33–42. doi:10.1016/j.dnarep.2015.04.011. PMC . PMID 26021671.
- Sjolund AB, Senejani AG, Sweasy JB (2013). "MBD4 and TDG: multifaceted DNA glycosylases with ever expanding biological roles". Mutation Research. 743–744: 12–25. doi:10.1016/j.mrfmmm.2012.11.001. PMC . PMID 23195996.
- Cooper DN, Youssoufian H (Feb 1988). "The CpG dinucleotide and human genetic disease". Human Genetics. 78 (2): 151–5. doi:10.1007/bf00278187. PMID 3338800.
- Howard JH, Frolov A, Tzeng CW, Stewart A, Midzak A, Majmundar A, Godwin A, Heslin M, Bellacosa A, Arnoletti JP (Jan 2009). "Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer". Cancer Biology & Therapy. 8 (1): 94–100. doi:10.4161/cbt.8.1.7469. PMC . PMID 19127118.
- Tricarico R, Cortellino S, Riccio A, Jagmohan-Changur S, Van der Klift H, Wijnen J, Turner D, Ventura A, Rovella V, Percesepe A, Lucci-Cordisco E, Radice P, Bertario L, Pedroni M, Ponz de Leon M, Mancuso P, Devarajan K, Cai KQ, Klein-Szanto AJ, Neri G, Møller P, Viel A, Genuardi M, Fodde R, Bellacosa A (Oct 2015). "Involvement of MBD4 inactivation in mismatch repair-deficient tumorigenesis". Oncotarget. 6: 42892–904. doi:10.18632/oncotarget.5740. PMID 26503472.
- Xiong XD, Luo XP, Liu X, Jing X, Zeng LQ, Lei M, Hong XS, Chen Y (2012). "The MBD4 Glu346Lys polymorphism is associated with the risk of cervical cancer in a Chinese population". Int. J. Gynecol. Cancer. 22 (9): 1552–6. doi:10.1097/IGC.0b013e31826e22e4. PMID 23027038.
- Hegde ML, Hegde PM, Bellot LJ, Mandal SM, Hazra TK, Li GM, Boldogh I, Tomkinson AE, Mitra S (2013). "Prereplicative repair of oxidized bases in the human genome is mediated by NEIL1 DNA glycosylase together with replication proteins". Proc. Natl. Acad. Sci. U.S.A. 110 (33): E3090–9. doi:10.1073/pnas.1304231110. PMC . PMID 23898192.
- Nemec AA, Wallace SS, Sweasy JB (Oct 2010). "Variant base excision repair proteins: contributors to genomic instability". Seminars in Cancer Biology. 20 (5): 320–8. doi:10.1016/j.semcancer.2010.10.010. PMC . PMID 20955798.
- Suzuki T, Harashima H, Kamiya H (2010). "Effects of base excision repair proteins on mutagenesis by 8-oxo-7,8-dihydroguanine (8-hydroxyguanine) paired with cytosine and adenine". DNA Repair (Amst.). 9 (5): 542–50. doi:10.1016/j.dnarep.2010.02.004. PMID 20197241.
- Shinmura K, Tao H, Goto M, Igarashi H, Taniguchi T, Maekawa M, Takezaki T, Sugimura H (2004). "Inactivating mutations of the human base excision repair gene NEIL1 in gastric cancer". Carcinogenesis. 25 (12): 2311–7. doi:10.1093/carcin/bgh267. PMID 15319300.
- Chaisaingmongkol J, Popanda O, Warta R, Dyckhoff G, Herpel E, Geiselhart L, Claus R, Lasitschka F, Campos B, Oakes CC, Bermejo JL, Herold-Mende C, Plass C, Schmezer P (2012). "Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma". Oncogene. 31 (49): 5108–16. doi:10.1038/onc.2011.660. PMID 22286769.
- Do H, Wong NC, Murone C, John T, Solomon B, Mitchell PL, Dobrovic A (2014). "A critical re-assessment of DNA repair gene promoter methylation in non-small cell lung carcinoma". Scientific Reports. 4: 4186. doi:10.1038/srep04186. PMC . PMID 24569633.
- Farkas SA, Vymetalkova V, Vodickova L, Vodicka P, Nilsson TK (Apr 2014). "DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/β-catenin signaling pathway genes". Epigenomics. 6 (2): 179–91. doi:10.2217/epi.14.7. PMID 24811787.
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Uracil DNA glycosylase superfamily Provide feedback
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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
Internal database links
|Similarity to PfamA using HHSearch:||DUF4918|
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].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Aravind L|
|Number in seed:||148|
|Number in full:||18647|
|Average length of the domain:||160.40 aa|
|Average identity of full alignment:||21 %|
|Average coverage of the sequence by the domain:||65.03 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
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a FASTA-format file
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 154 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 sequence.
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