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Wikipedia

DNA glycosylase

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.[1]

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.[2][3]

Monofunctional vs. bifunctional glycosylases edit

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.[4] Some glycosylase-lyases can further perform δ-elimination, which converts the 3' aldehyde to a 3' phosphate.

Biochemical mechanism edit

The first crystal structure of a DNA glycosylase was obtained for E. coli Nth.[5] 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 edit

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.[4]

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.

Glycosylases in bacteria, yeast and humans[6][7]
E. coli B. cereus Yeast (S. cerevisiae) Human Type Substrates
AlkA AlkE Mag1 MPG (N-methylpurine DNA glycosylase) monofunctional 3-meA(3-alkyladenine), hypoxanthine
UDG Ung1 UNG monofunctional uracil
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)
Ntg2
Nei Not present hNEIL1 bifunctional Tg, hoU, hoC, urea, FapyG, FapyA(4,6-diamino-5-formamidopyrimidine)
hNEIL2 AP site, hoU
hNEIL3 unknown
MutY Not present hMYH monofunctional A:8-oxoG
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 edit

 
Structure of the base-excision repair enzyme uracil-DNA glycosylase. The uracil residue is shown in yellow.

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.[8]

This entry represents various uracil-DNA glycosylases and related DNA glycosylases (EC), such as uracil-DNA glycosylase,[9] thermophilic uracil-DNA glycosylase,[10] G:T/U mismatch-specific DNA glycosylase (Mug),[11] and single-strand selective monofunctional uracil-DNA glycosylase (SMUG1).[12]

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.[13] 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.[14] 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.[15]

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.[16] UDG undergoes a conformational change from an ‘‘open’’ unbound state to a ‘‘closed’’ DNA-bound state.[17]

UDG
 
Epstein–Barr virus uracil-dna glycosylase in complex with ugi from pbs-2
Identifiers
SymbolUDG
PfamPF03167
InterProIPR005122
PROSITEPDOC00121
SCOP21udg / SCOPe / SUPFAM
CDDcd09593
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

History edit

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.[8]

Function edit

The function of UDG is to remove mutations in DNA, more specifically removing uracil.

Structure edit

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.[9]

Mechanism edit

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.[18] These aberrant uracil residues are genotoxic.[19]

Localisation edit

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.[20]

Conservation edit

The sequence of uracil-DNA glycosylase is extremely well conserved[21] in bacteria and eukaryotes as well as in herpes viruses. More distantly related uracil-DNA glycosylases are also found in poxviruses.[22] 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[23] to act as a general base in the catalytic mechanism.

Family edit

There are two UDG families, named Family 1 and Family 2. Family 1 is active against uracil in ssDNA and dsDNA. Family 2 excise uracil from mismatches with guanine.[8]

Glycosylases of oxidized bases edit

 
8-oxoG (syn) in a Hoogsteen base pair with dA (anti)

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.[24] 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.[25] 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 edit

This group includes E. coli AlkA and related proteins in higher eukaryotes. These glycosylases are monofunctional and recognize methylated bases, such as 3-methyladenine.

AlkA edit

AlkA refers to 3-methyladenine DNA glycosylase II.[26]

Pathology edit

Epigenetic deficiencies in cancers edit

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).[citation needed] Two examples of epimutations in DNA glycosylase genes that occur in cancers are summarized below.

MBD4 edit

 
Hydrolysis of cytosine to uracil

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.[28] 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.[29] 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.[30] 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.[30][31] 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.[30] Thus, a decrease in expression of MBD4 could cause an increase in carcinogenic mutations.

MBD4 expression is reduced in almost all colorectal neoplasms due to methylation of the promoter region of MBD4.[32] Also MBD4 is deficient due to mutation in about 4% of colorectal cancers,[33]

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.[32] 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.[34]

NEIL1 edit

Nei-like (NEIL) 1 is a DNA glycosylase of the Nei family (which also contains NEIL2 and NEIL3).[35] 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.[35]

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.[36] 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.[37]

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.[38] 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.[39] 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.[39]

When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors, 42% were hypermethylated in the NEIL1 promoter region.[40] 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.[41]

References edit

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  41. ^ 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.
This article incorporates text from the public domain Pfam and InterPro: IPR005122

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glycosylase, family, enzymes, involved, base, excision, repair, classified, under, number, base, excision, repair, mechanism, which, damaged, bases, removed, replaced, catalyze, first, step, this, process, they, remove, damaged, nitrogenous, base, while, leavi. 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 1 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 2 3 Contents 1 Monofunctional vs bifunctional glycosylases 2 Biochemical mechanism 3 Types of glycosylases 3 1 Uracil DNA glycosylases 4 History 5 Function 6 Structure 7 Mechanism 8 Localisation 9 Conservation 10 Family 10 1 Glycosylases of oxidized bases 10 2 Glycosylases of alkylated bases 10 2 1 AlkA 11 Pathology 12 Epigenetic deficiencies in cancers 12 1 MBD4 12 2 NEIL1 13 References 14 External linksMonofunctional vs bifunctional glycosylases editThere 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 b Elimination of an AP site by a glycosylase lyase yields a 3 a b unsaturated aldehyde adjacent to a 5 phosphate which differs from the AP endonuclease cleavage product 4 Some glycosylase lyases can further perform d elimination which converts the 3 aldehyde to a 3 phosphate Biochemical mechanism editThe first crystal structure of a DNA glycosylase was obtained for E coli Nth 5 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 editCrystal 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 4 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 Glycosylases in bacteria yeast and humans 6 7 E coli B cereus Yeast S cerevisiae Human Type Substrates AlkA AlkE Mag1 MPG N methylpurine DNA glycosylase monofunctional 3 meA 3 alkyladenine hypoxanthine UDG Ung1 UNG monofunctional uracil 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 Ntg2 Nei Not present hNEIL1 bifunctional Tg hoU hoC urea FapyG FapyA 4 6 diamino 5 formamidopyrimidine hNEIL2 AP site hoU hNEIL3 unknown MutY Not present hMYH monofunctional A 8 oxoG 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 edit nbsp Structure of the base excision repair enzyme uracil DNA glycosylase The uracil residue is shown in yellow 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 8 This entry represents various uracil DNA glycosylases and related DNA glycosylases EC such as uracil DNA glycosylase 9 thermophilic uracil DNA glycosylase 10 G T U mismatch specific DNA glycosylase Mug 11 and single strand selective monofunctional uracil DNA glycosylase SMUG1 12 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 13 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 14 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 15 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 16 UDG undergoes a conformational change from an open unbound state to a closed DNA bound state 17 UDG nbsp Epstein Barr virus uracil dna glycosylase in complex with ugi from pbs 2IdentifiersSymbolUDGPfamPF03167InterProIPR005122PROSITEPDOC00121SCOP21udg SCOPe SUPFAMCDDcd09593Available protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summaryHistory editLindahl 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 8 Function editThe function of UDG is to remove mutations in DNA more specifically removing uracil Structure editThese 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 9 Mechanism editUracil 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 18 These aberrant uracil residues are genotoxic 19 Localisation editIn 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 20 Conservation editThe sequence of uracil DNA glycosylase is extremely well conserved 21 in bacteria and eukaryotes as well as in herpes viruses More distantly related uracil DNA glycosylases are also found in poxviruses 22 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 23 to act as a general base in the catalytic mechanism Family editThere are two UDG families named Family 1 and Family 2 Family 1 is active against uracil in ssDNA and dsDNA Family 2 excise uracil from mismatches with guanine 8 Glycosylases of oxidized bases edit nbsp 8 oxoG syn in a Hoogsteen base pair with dA anti 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 24 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 25 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 edit This group includes E coli AlkA and related proteins in higher eukaryotes These glycosylases are monofunctional and recognize methylated bases such as 3 methyladenine AlkA edit AlkA refers to 3 methyladenine DNA glycosylase II 26 Pathology editDNA glycosylases involved in base excision repair BER may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers 27 Epigenetic deficiencies in cancers editEpigenetic 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 citation needed Two examples of epimutations in DNA glycosylase genes that occur in cancers are summarized below MBD4 edit nbsp Hydrolysis of cytosine to uracil 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 28 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 29 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 30 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 30 31 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 30 Thus a decrease in expression of MBD4 could cause an increase in carcinogenic mutations MBD4 expression is reduced in almost all colorectal neoplasms due to methylation of the promoter region of MBD4 32 Also MBD4 is deficient due to mutation in about 4 of colorectal cancers 33 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 32 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 34 NEIL1 edit Nei like NEIL 1 is a DNA glycosylase of the Nei family which also contains NEIL2 and NEIL3 35 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 35 NEIL1 protein recognizes targets and removes certain oxidatively damaged bases and then incises the abasic site via b d 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 36 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 37 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 38 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 39 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 39 When 8 DNA repair genes were evaluated in non small cell lung cancer NSCLC tumors 42 were hypermethylated in the NEIL1 promoter region 40 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 41 References edit Lindahl T 1986 DNA Glycosylases in DNA Repair Mechanisms of DNA Damage and Repair Vol 38 pp 335 340 doi 10 1007 978 1 4615 9462 8 36 ISBN 978 1 4615 9464 2 PMID 3527146 a href Template Cite book html title Template Cite book cite book a journal ignored help 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 Bibcode 2006PNAS 10311796A doi 10 1073 pnas 0603563103 PMC 1544249 PMID 16864782 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 3 339 344 doi 10 5511 plantbiotechnology 24 339 a b 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 Bibcode 1992Sci 258 434K 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 a b c 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 a b 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 S2CID 14851787 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 S2CID 32822653 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 S2CID 9136303 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 doi 10 1016 S0021 9258 19 76470 9 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 521670 PMID 15466595 Wu Peiying Qiu Chen Sohail Anjum Zhang Xing Bhagwat Ashok S Cheng Xiaodong 2003 02 14 Mismatch repair in methylated DNA Structure and activity of the mismatch specific thymine glycosylase domain of methyl CpG binding protein MBD4 The Journal of Biological Chemistry 278 7 5285 5291 doi 10 1074 jbc M210884200 ISSN 0021 9258 PMC 2764232 PMID 12456671 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 137523 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 S2CID 14851787 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 Pena 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 doi 10 1002 j 1460 2075 1989 tb08464 x 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 Bibcode 1993PNAS 90 4518U 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 Bibcode 1995Natur 373 487S doi 10 1038 373487a0 PMID 7845459 S2CID 4315434 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 Bibcode 1999PNAS 9613300K doi 10 1073 pnas 96 23 13300 PMC 23942 PMID 10557315 Russo Maria Teresa De Luca Gabriele Degan Paolo Parlanti Eleonora Dogliotti Eugenia Barnes Deborah E Lindahl Tomas Yang Hanjing Miller Jeffrey H Bignami Margherita 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 2012 Structure function studies of an unusual 3 methyladenine DNA glycosylase II AlkA from Deinococcus radiodurans Acta Crystallogr D 68 6 703 12 doi 10 1107 S090744491200947X PMID 22683793 Osorio A Milne R L Kuchenbaecker K Vaclova T Pita G Alonso R Peterlongo P Blanco I de la Hoya M Duran M Diez O Ramon y Cajal T Konstantopoulou I Martinez Bouzas C Andres 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 3974638 PMID 24698998 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 PMC 4176167 PMID 25183517 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 4903958 PMID 26021671 a b c 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 3661743 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 S2CID 41948691 a b 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 amp Therapy 8 1 94 100 doi 10 4161 cbt 8 1 7469 PMC 2683899 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 Moller P Viel A Genuardi M Fodde R Bellacosa A Oct 2015 Involvement of MBD4 inactivation in mismatch repair deficient tumorigenesis PDF Oncotarget 6 40 42892 904 doi 10 18632 oncotarget 5740 PMC 4767479 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 S2CID 788490 a b 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 Bibcode 2013PNAS 110E3090H doi 10 1073 pnas 1304231110 PMC 3746843 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 3254599 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 hdl 2115 43021 PMID 20197241 S2CID 207147128 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 a b 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 Bibcode 2014NatSR 4E4186D doi 10 1038 srep04186 PMC 3935198 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 b catenin signaling pathway genes Epigenomics 6 2 179 91 doi 10 2217 epi 14 7 PMID 24811787 This article incorporates text from the public domain Pfam and InterPro IPR005122External links edit nbsp Media related to DNA glycosylase at Wikimedia Commons DNA Glycosylases at the U S National Library of Medicine Medical Subject Headings MeSH Portal nbsp Biology Retrieved from https en wikipedia org w index php title DNA glycosylase amp oldid 1188126881, wikipedia, wiki, book, books, library,

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