Page last updated: 2024-10-24

DNA alkylation repair

Definition

Target type: biologicalprocess

The repair of alkylation damage in DNA, e.g. the removal of a non-physiological alkyl group from a nucleobase. This is usually mediated by DNA alkyltransferases. [PMID:10946226, PMID:35543797]

DNA alkylation repair is a cellular process that removes alkyl groups from DNA, which are damaging modifications that can lead to mutations and cancer. Alkylation occurs when an alkyl group (e.g., methyl, ethyl, or propyl) is added to a base in DNA, typically at the N7 position of guanine or the O6 position of guanine. These modifications disrupt the normal base pairing of DNA, leading to errors in replication and transcription. The repair of alkylated DNA involves two main pathways: direct reversal and base excision repair (BER).

Direct reversal involves the removal of the alkyl group directly from the damaged base, without removing the base itself. This is accomplished by enzymes called alkyltransferases, which transfer the alkyl group to a cysteine residue on their own protein. The most well-studied alkyltransferase is O6-methylguanine-DNA methyltransferase (MGMT), which removes methyl groups from the O6 position of guanine.

BER is a more complex pathway that involves multiple enzymes and is responsible for removing a wide range of damaged bases, including alkylated bases. In BER, the damaged base is first recognized and removed by a DNA glycosylase enzyme. This leaves an apurinic/apyrimidinic (AP) site in the DNA backbone. The AP site is then cleaved by an AP endonuclease, creating a single-strand break. The gap is then filled by a DNA polymerase, using the undamaged strand as a template, and the nick is sealed by DNA ligase.

The choice between direct reversal and BER depends on the specific type of alkylation damage. For example, MGMT is highly effective at removing methyl groups from O6-guanine, but it is not effective at removing larger alkyl groups. In these cases, BER is the primary repair pathway.

DNA alkylation repair is essential for maintaining the integrity of the genome. Defects in this pathway can lead to increased mutation rates, genomic instability, and an increased risk of cancer. For example, mutations in MGMT have been linked to increased risk of glioblastoma, a type of brain cancer.

In addition to these two main pathways, there are other mechanisms that contribute to DNA alkylation repair, including nucleotide excision repair (NER), mismatch repair (MMR), and translesion synthesis (TLS). NER removes bulky DNA lesions, including some alkylated bases. MMR repairs mismatches in DNA that can arise from replication errors or from alkylation damage. TLS is a process that allows DNA replication to proceed past damaged bases, even if they are not repaired.

The repair of alkylated DNA is a complex process that involves multiple enzymes and pathways. These pathways work together to ensure that DNA damage is efficiently repaired and that the integrity of the genome is maintained.'
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Proteins (5)

ProteinDefinitionTaxonomy
Alpha-ketoglutarate-dependent dioxygenase FTOAn alpha-ketoglutarate-dependent dioxygenase FTO that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9C0B1]Homo sapiens (human)
Ubiquitin carboxyl-terminal hydrolase 7A ubiquitin carboxyl-terminal hydrolase 7 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q93009]Homo sapiens (human)
Probable ubiquitin carboxyl-terminal hydrolase FAF-XA probable ubiquitin carboxyl-terminal hydrolase FAF-X that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q93008]Homo sapiens (human)
DNA-3-methyladenine glycosylaseA DNA-3-methyladenine glycosylase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P29372]Homo sapiens (human)
Methylated-DNA--protein-cysteine methyltransferaseA methylated-DNA--protein-cysteine methyltransferase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P16455]Homo sapiens (human)

Compounds (34)

CompoundDefinitionClassesRoles
citric acid, anhydrouscitric acid : A tricarboxylic acid that is propane-1,2,3-tricarboxylic acid bearing a hydroxy substituent at position 2. It is an important metabolite in the pathway of all aerobic organisms.

Citric Acid: A key intermediate in metabolism. It is an acid compound found in citrus fruits. The salts of citric acid (citrates) can be used as anticoagulants due to their calcium chelating ability.
tricarboxylic acidantimicrobial agent;
chelator;
food acidity regulator;
fundamental metabolite
malic acid2-hydroxydicarboxylic acid : Any dicarboxylic acid carrying a hydroxy group on the carbon atom at position alpha to the carboxy group.

malic acid : A 2-hydroxydicarboxylic acid that is succinic acid in which one of the hydrogens attached to a carbon is replaced by a hydroxy group.
2-hydroxydicarboxylic acid;
C4-dicarboxylic acid
food acidity regulator;
fundamental metabolite
pyruvic acidpyruvic acid : A 2-oxo monocarboxylic acid that is the 2-keto derivative of propionic acid. It is a metabolite obtained during glycolysis.

Pyruvic Acid: An intermediate compound in the metabolism of carbohydrates, proteins, and fats. In thiamine deficiency, its oxidation is retarded and it accumulates in the tissues, especially in nervous structures. (From Stedman, 26th ed)
2-oxo monocarboxylic acidcofactor;
fundamental metabolite
aurintricarboxylic acidaurintricarboxylic acid : A member of the class of quinomethanes that is 3-methylidene-6-oxocyclohexa-1,4-diene-1-carboxylic acid in which the methylidene hydrogens are replaced by 4-carboxy-3-hydroxyphenyl groups. The trisodium salt is the biological stain 'chrome violet CG' while the triammonium salt is 'aluminon'.

Aurintricarboxylic Acid: A dye which inhibits protein biosynthesis at the initial stages. The ammonium salt (aluminon) is a reagent for the colorimetric estimation of aluminum in water, foods, and tissues.
monohydroxybenzoic acid;
quinomethanes;
tricarboxylic acid
fluorochrome;
histological dye;
insulin-like growth factor receptor 1 antagonist
gossypolGossypol: A dimeric sesquiterpene found in cottonseed (GOSSYPIUM). The (-) isomer is active as a male contraceptive (CONTRACEPTIVE AGENTS, MALE) whereas toxic symptoms are associated with the (+) isomer.
nu2058NU2058: structure in first source
o(6)-benzylguanineO(6)-benzylguanine: a suicide inhibitor of O(6)-methylguanine-DNA methyltransferase activity
2,4-pyridinedicarboxylic acidlutidinic acid : A pyridinedicarboxylic acid carrying carboxy groups at positions 2 and 4.pyridinedicarboxylic acid
d-glutamateD-alpha-amino acid;
glutamic acid
Escherichia coli metabolite;
mouse metabolite
glutamic acidglutamic acid : An alpha-amino acid that is glutaric acid bearing a single amino substituent at position 2.

Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid is the most common excitatory neurotransmitter in the CENTRAL NERVOUS SYSTEM.
glutamic acid;
glutamine family amino acid;
L-alpha-amino acid;
proteinogenic amino acid
Escherichia coli metabolite;
ferroptosis inducer;
micronutrient;
mouse metabolite;
neurotransmitter;
nutraceutical
mitoxantrone hydrochloridehydrochlorideantineoplastic agent
d-lactic acid(R)-lactic acid : An optically active form of lactic acid having (R)-configuration.2-hydroxypropanoic acidEscherichia coli metabolite;
human metabolite
ursolic acidhydroxy monocarboxylic acid;
pentacyclic triterpenoid
geroprotector;
plant metabolite
o-(6)-methylguanine6-O-methylguanine : A methylguanine in which the methyl group is positioned on the oxygen at position 6. Formed in DNA by alkylation of the oxygen atom of guanine, most often by N-nitroso compounds and sometimes due to methylation by other compounds such as endogenous S-adenosylmethionine, it base-pairs to thymine rather than cytidine, causing a G:C to A:T transition in DNA.

methylguanine : A 2-aminopurine that is guanine bearing a single methyl substituent.

O-(6)-methylguanine: structure
methylguaninemutagen
o(6)-n-butylguanine
6-ethylguanine6-ethylguanine: found in rat brain DNA
xestoquinonexestoquinone: structure given in first source; RN given refers to the (S)-isomer; RN for cpd without isomeric designation not available 5/91; isolated from the sea sponge Xestospongia sapra
o(6)-benzyl-2'-deoxyguanosine
2,4-diamino-6-benzyloxy-5-nitrosopyrimidine2,4-diamino-6-benzyloxy-5-nitrosopyrimidine: inhibits O(6)-alkylguanine-DNA alkyltransferase; structure given in first source
bardoxolone methylmethyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate: structure in first sourcecyclohexenones
d-2-hydroxyglutarate(R)-2-hydroxyglutaric acid : The (R)-enantiomer of 2-hydroxyglutaric acid.2-hydroxyglutaric acidalgal metabolite
alpha-hydroxyglutarate, (l)-isomer2-hydroxyglutaric acid
fumaric acidfumaric acid : A butenedioic acid in which the C=C double bond has E geometry. It is an intermediate metabolite in the citric acid cycle.

fumaric acid: see also record for ferrous fumarate; use FUMARATES for general fumaric acid esters
butenedioic acidfood acidity regulator;
fundamental metabolite;
geroprotector
5-carboxy-8-hydroxyquinoline5-carboxy-8-hydroxyquinoline: a JmjC histone demethylase inhibitor; structure in first sourcequinolines
aconitic acidcis-aconitic acid : The cis-isomer of aconitic acid.aconitic acidfundamental metabolite
p5091P5091: inhibits ubiquitin-specific protease 7; structure in first source
lomeguatrib
oxalylglycineN-oxalylglycine : An amino dicarboxylic acid that is iminodiacetic acid with an oxo substituent. It is used as an inhibitor of alpha-ketoglutarate dependent (EC 1.14.11.*) enzymes.

oxalylglycine: structure given in first source
amino dicarboxylic acid;
N-acylglycine
EC 1.14.11.* (oxidoreductase acting on paired donors, 2-oxoglutarate as one donor, incorporating 1 atom each of oxygen into both donors) inhibitor
entacaponeentacapone : A monocarboxylic acid amide that is N,N-diethylprop-2-enamide in which the hydrogen at position 2 is substituted by a cyano group and the hydrogen at the 3E position is substituted by a 3,4-dihydroxy-5-nitrophenyl group.

entacapone: structure given in first source
2-nitrophenols;
catechols;
monocarboxylic acid amide;
nitrile
antidyskinesia agent;
antiparkinson drug;
central nervous system drug;
EC 2.1.1.6 (catechol O-methyltransferase) inhibitor
morinmorin : A pentahydroxyflavone that is 7-hydroxyflavonol bearing three additional hydroxy substituents at positions 2' 4' and 5.

morin: a light yellowish pigment found in the wood of old fustic (Chlorophora tinctoria)
7-hydroxyflavonol;
pentahydroxyflavone
angiogenesis modulating agent;
anti-inflammatory agent;
antibacterial agent;
antihypertensive agent;
antineoplastic agent;
antioxidant;
EC 5.99.1.2 (DNA topoisomerase) inhibitor;
hepatoprotective agent;
metabolite;
neuroprotective agent
degrasyndegrasyn: a JAK2 kinase inhibitor that induces rapid degradation of c-Myc protein in MM-1 multiple myeloma and other tumor cell lines; structure in first source
fg-4592roxadustat : An N-acylglycine resulting from the formal condensation of the amino group of glycine with the carboxy group of 4-hydroxy-1-methyl-7-phenoxyisoquinoline-3-carboxylic acid. It is an inhibitor of hypoxia inducible factor prolyl hydroxylase (HIF-PH).

roxadustat: structure in first source
aromatic ether;
isoquinolines;
N-acylglycine
EC 1.14.11.2 (procollagen-proline dioxygenase) inhibitor;
EC 1.14.11.29 (hypoxia-inducible factor-proline dioxygenase) inhibitor
hbx 41108HBX 41,108: inhibits USP7 ubiquitin protease; structure in first source
1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone: a USP7 inhibitor; structure in first source