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catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
DNA polymerase beta (Pol beta) catalyzes both DNA synthesis at the 3'-hydroxyl terminus and esxcision of 5'-dRP moiety prior to completion of the base excsion repair (BER) by DNA ligase
-
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
DNA polymerase beta as the major polymerase involved in repair of oxidative base lesions, in single nucleotide replacement mechanisms. The 5'-deoxyribosephosphate lyase activity of Pol beta is essential for repair
-
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
enzyme is involved in single-nucleotide base excision DNA repair, SN-BER
-
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
homologous to the dRP lyase activity of polymerase beta, pol beta. Proposed to participate in single-nucleotide base excision repair in mammalian cells, which is the major repair pathway in eukaryotic cells responsible for repair of lesions that give rise to abasic siles in DNA
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
in reactions reconstituted with uracil-DNA glycosylase, apurinic/apyrimidinic endonuclease and ligase I, pol iota can use its dRP lyase and polymerase activities to repair G-U and A-U pairs in DNA, a specialized form of base excision repair, BER. pol iota has an intrinsic dRP lyase activity and the reactions proceeds via beta-elimination involving an active residue containing a primary amine
-
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
reaction is part of the DNA base excision repair BER, enzyme releases 5'-terminal deoxyribose phosphate from preincised apurinic/apyrimidinic site DNA by beta-elimination
-
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site
the catalytic subunit of pol gamma catalyzes the release of the the 5'-deoxyribose phosphate residue from incised apurinic/apyrimidinic sites to produce a substrate for DNA ligase. The ability to trap covalent enzyme DNA complexes with NaBH4 implicates Schiff base intermediate in an beta-elimination reaction mechanism
-
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49-residue oligonucleotide duplex DNA
? + 2-deoxy-D-ribose 5-phosphate
substrate contains uracil residue at position 21. The DNA is pretreated with uracil DNA glycosylase and AP endonuclease
-
-
?
5'-deoxyribose phosphate DNA substrate
?
-
-
-
?
labeled uracil-containing DNA
? + 2-deoxy-D-ribose 5-phosphate
[32P]-labeled, treated with with uracil-DNA glycosylase and apurinic/apyrimidinic endonuclease
-
-
?
34-bp oligonucleotide containing uracil at position 16
? + 2-deoxy-D-ribose 5-phosphate
labelled with 3'-end by terminal deoxynucleotidyltransferase using [alpha-32P]ddATP and annealed to its complementary oligonucleotide, and pretreated with human uracil-DNA glycosylase and AP endonuclease
-
-
?
34-bp-deoxyoligonucleotide duplex containing a uracil residue at position 16
? + 2-deoxy-D-ribose phosphate
-
preincised [32P] apurinic/apyrimidinic site containing DNA, pretreated with uracil DNA-glycosylase and AP endonuclease
the reaction products are separarted by electrophoresis
-
?
35-bp-deoxyoligonucleotide duplex containing a uracil residue at position 15
? + 2-deoxy-D-ribose phosphate
-
in vitro single-nucleotide base excision DNA repair assay, containing amongst others uracil DNA-glycosylase, AP endonuclease and ligase I
-
-
?
49-bp oligodeoxynucleotide containing uracil at position 21
? + 2-deoxy-D-ribose 5-phosphate
-
labelled at 3'-end with [alpha-32P]ddATP by terminal deoxynucleotidyl transferase and annealed to an unlabelled complementary strand containing a G residue opposite the uracil. Before use, the substrate is treated with uracil-DNA glycosylase and AP endonuclease to generate a single nucleotide gap directly upstream from the labelled fragment containing a deoxyribose phosphate flap
-
-
?
closed-circular double-stranded DNA substrate bearing a single 8-oxoguanine/cytosine base pair at a defined position
? + 2-deoxy-D-ribose 5-phosphate
-
-
-
-
?
closed-circular double-stranded DNA substrate bearing a single dihydrouracil/guanine base pair at a defined position
? + 2-deoxy-D-ribose 5-phosphate
-
-
-
-
?
DNA with a 5'-incised apurinic/apyrimidinic site at position 21
? + 2-deoxy-D-ribose 5-phosphate
-
the uracil-DNA glycosylase-reacted DNA substrate is treated with AP endonuclease in the presence of MgCl2 to create a substrate containing a 5'-incised apurinic/apyrimidinic site. The resulting DNA substrate with a deoxyribose phosphate moiety at the 5'-end and a phosphate at the 3'-terminus is incubated with beta-pol or its amino-terminal 8-kDa domain
beta-pol is proposed to catalyze the release of the 5'-deoxyribose phosphate moiety from the cleaved apurinic/apyrimidinic site via a beta-elimination mechanism, producing 4-hydroxy-2-pentenal-5-phosphate
-
?
preincised apurinic/apyrimidinic DNA
?
-
-
-
-
?
additional information
?
-
additional information
?
-
in addition to removal of 5'-deoxyribose phosphate from base excision repair intermediates, enzyme also removes 5'-adenylated deoxyribose phosphate from base excision repair intermediates after abortive ligation
-
-
?
additional information
?
-
catalysis of the beta-elimination of the 5' deoxyribose-5-phosphate at an abasic site in DNA where a DNA-(apurinic or apyrimidinic site) lyase has already cleaved the C-O-P bond 3' to the apurinic or apyrimidinic site. The reaction mechanism of the lyase reaction involves a transient covalent enzyme-DNA intermediate in the form of a Schiff base connecting Lys72 of the enzyme with the 5'-dRP moiety. The Schiff base intermediate is resolved via a beta-elimination reaction, initiated by abstraction of a C2'-H atom from the 5'-deoxyribose phosphate (5'-dRP) moiety
-
-
?
additional information
?
-
-
reaction is part of the DNA base excision repair BER
-
-
?
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Aberrant Crypt Foci
Folate deficiency provides protection against colon carcinogenesis in DNA polymerase {beta} haploinsufficient mice.
Adenocarcinoma
DNA polymerase beta expression differences in selected human tumors and cell lines.
Adenoma
Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk.
Adenoma
Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3.
Adenoma
Rapid recognition of aberrant dHPLC elution profiles using the Transgenomic Navigator software.
Brain Neoplasms
Elevated expression of DNA polymerase beta gene in glioma cell lines with acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea.
Breast Neoplasms
Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers.
Breast Neoplasms
DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
Breast Neoplasms
Genetic variations in 3'UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response.
Breast Neoplasms
PEG-functionalized zinc oxide nanoparticles induce apoptosis in breast cancer cells through reactive oxygen species-dependent impairment of DNA damage repair enzyme NEIL2.
Breast Neoplasms
Perturbation of base excision repair sensitizes breast cancer cells to APOBEC3 deaminase-mediated mutations.
Burkitt Lymphoma
Detection of genomic aberrations in molecularly defined Burkitt lymphoma by array-based high resolution single nucleotide polymorphism analysis.
Carcinogenesis
Cervical carcinoma risk associate with genetic polymorphisms of NEIL2 gene in Chinese population and its significance as predictive biomarker.
Carcinogenesis
DNA polymerase beta expression differences in selected human tumors and cell lines.
Carcinogenesis
Folate deficiency provides protection against colon carcinogenesis in DNA polymerase {beta} haploinsufficient mice.
Carcinogenesis
Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.
Carcinoma
Cervical carcinoma risk associate with genetic polymorphisms of NEIL2 gene in Chinese population and its significance as predictive biomarker.
Carcinoma
Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.
Carcinoma
Overexpression of DNA polymerase iota (Pol?) in esophageal squamous cell carcinoma.
Carcinoma, Hepatocellular
Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1.
Carcinoma, Hepatocellular
Polymorphisms of base-excision repair genes and the hepatocarcinogenesis.
Carcinoma, Squamous Cell
Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.
Cataract
A variant in a microRNA binding site in NEIL2 3'UTR confers susceptibility to age-related cataracts.
Cataract
Regulated over-expression of DNA polymerase beta mediates early onset cataract in mice.
Cockayne Syndrome
Cockayne Syndrome group B protein stimulates NEIL2 DNA glycosylase activity.
Cockayne Syndrome
Neil2-null Mice Accumulate Oxidized DNA Bases in the Transcriptionally Active Sequences of the Genome and Are Susceptible to Innate Inflammation.
Colonic Neoplasms
DNA polymerase beta expression differences in selected human tumors and cell lines.
Colorectal Neoplasms
Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition.
Colorectal Neoplasms
Genetic variations in 3'UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response.
Colorectal Neoplasms
Sirt3 regulates the level of mitochondrial DNA repair activity through deacetylation of NEIL1, NEIL2, OGG1, MUTYH, APE1 and LIG3 in colorectal cancer.
Cryptorchidism
Effect of busulphan treatment and elevated temperature on the expression of the beta-pol gene in rat testis.
dna 5'-deoxyribose phosphate lyase deficiency
Cells deficient in DNA polymerase beta are hypersensitive to alkylating agent-induced apoptosis and chromosomal breakage.
dna 5'-deoxyribose phosphate lyase deficiency
The deoxyribose phosphate lyase of DNA polymerase ? suppresses a processive DNA synthesis to prevent trinucleotide repeat instability.
Glioma
Elevated expression of DNA polymerase beta gene in glioma cell lines with acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea.
Hepatitis C
Polymorphisms of base-excision repair genes and the hepatocarcinogenesis.
Herpes Simplex
The replicative DNA polymerase of herpes simplex virus 1 exhibits apurinic/apyrimidinic and 5'-deoxyribose phosphate lyase activities.
Hypersensitivity
Base excision repair intermediates induce p53-independent cytotoxic and genotoxic responses.
Hypersensitivity
Cells deficient in DNA polymerase beta are hypersensitive to alkylating agent-induced apoptosis and chromosomal breakage.
Hypersensitivity
Hypersensitivity of DNA polymerase beta null mouse fibroblasts reflects accumulation of cytotoxic repair intermediates from site-specific alkyl DNA lesions.
Hypersensitivity
Identification of small molecule synthetic inhibitors of DNA polymerase beta by NMR chemical shift mapping.
Hypersensitivity
Mammalian DNA beta-polymerase in base excision repair of alkylation damage.
Hypersensitivity
The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity.
Infections
Helicobacter pylori infection downregulates the DNA glycosylase NEIL2, resulting in increased genome damage and inflammation in gastric epithelial cells.
Infections
Roles of conserved residues within the pre-NH2-terminal domain of herpes simplex virus 1 DNA polymerase in replication and latency in mice.
Infections
The DNA Glycosylase NEIL2 Suppresses Fusobacterium-Infection-Induced Inflammation and DNA Damage in Colonic Epithelial Cells.
Infections
The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase.
Lung Neoplasms
Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2.
Lung Neoplasms
NEIL2 Protects against Oxidative DNA Damage Induced by Sidestream Smoke in Human Cells.
Lymphoma
The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase.
Lymphoma, AIDS-Related
The HIV-1 transactivator protein Tat is a potent inducer of the human DNA repair enzyme beta-polymerase.
Nasopharyngeal Carcinoma
Salinomycin enhances radiotherapy sensitivity and reduces expressions of BIRC5 and NEIL2 in nasopharyngeal carcinoma.
Neoplasms
Abnormal Expressions of DNA Glycosylase Genes NEIL1, NEIL2, and NEIL3 Are Associated with Somatic Mutation Loads in Human Cancer.
Neoplasms
Alternative splicing of DNA polymerase beta mRNA is not tumor-specific.
Neoplasms
Cervical carcinoma risk associate with genetic polymorphisms of NEIL2 gene in Chinese population and its significance as predictive biomarker.
Neoplasms
DNA polymerase beta expression differences in selected human tumors and cell lines.
Neoplasms
DNA polymerases during tumor growth.
Neoplasms
Elevated expression of DNA polymerase beta gene in glioma cell lines with acquired resistance to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea.
Neoplasms
Folate deficiency provides protection against colon carcinogenesis in DNA polymerase {beta} haploinsufficient mice.
Neoplasms
Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.
Neoplasms
Genetic variations in 3'UTRs of SMUG1 and NEIL2 genes modulate breast cancer risk, survival and therapy response.
Neoplasms
Genomic landscape of DNA repair genes in cancer.
Neoplasms
Haploinsufficiency in DNA polymerase beta increases cancer risk with age and alters mortality rate.
Neoplasms
Identification of novel mRNA isoforms for human DNA polymerase beta.
Neoplasms
PEG-functionalized zinc oxide nanoparticles induce apoptosis in breast cancer cells through reactive oxygen species-dependent impairment of DNA damage repair enzyme NEIL2.
Neoplasms
Regulated over-expression of DNA polymerase beta mediates early onset cataract in mice.
Neoplasms
Sirt3 regulates the level of mitochondrial DNA repair activity through deacetylation of NEIL1, NEIL2, OGG1, MUTYH, APE1 and LIG3 in colorectal cancer.
Neoplasms
Transcriptional upregulation of DNA polymerase beta by TEIF.
Neoplasms
Unique Structural Features of Mammalian NEIL2 DNA Glycosylase Prime Its Activity for Diverse DNA Substrates and Environments.
Neoplasms
Viral integration in BK polyomavirus-associated urothelial carcinoma in renal transplant recipients: multistage carcinogenesis revealed by next-generation virome capture sequencing.
Neuroblastoma
Specific Inhibition of NEIL-initiated repair of oxidized base damage in human genome by copper and iron: potential etiological linkage to neurodegenerative diseases.
Oropharyngeal Neoplasms
Functional variants of the NEIL1 and NEIL2 genes and risk and progression of squamous cell carcinoma of the oral cavity and oropharynx.
Ovarian Neoplasms
DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
Prion Diseases
DNA glycosylase Neil2 contributes to genomic responses in the spleen during clinical prion disease.
Rectal Neoplasms
REG4, NEIL2, and BIRC5 gene expression correlates with gamma-radiation sensitivity in patients with rectal cancer receiving radiotherapy.
Stomach Neoplasms
Genetic Variation of BCL2 (rs2279115), NEIL2 (rs804270), LTA (rs909253), PSCA (rs2294008) and PLCE1 (rs3765524, rs10509670) Genes and Their Correlation to Gastric Cancer Risk Based on Universal Tagged Arrays and Fe3O4 Magnetic Nanoparticles.
Stomach Neoplasms
Polymorphisms in NEIL-2, APE-1, CYP2E1 and MDM2 Genes are Independent Predictors of Gastric Cancer Risk in a Northern Jiangsu Population (China).
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additional information
study of the lyase activity of human DNA polymerase beta using analogues of the intermediate Schiff base complex
malfunction
Detection of stable DNA-protein crosslinks (DPC) between Pol beta and dL in intact cells. Formation of BER-mediated DNA-protein crosslinks, formation of oxidative polbeta-DPC in vivo. Pol beta-DPC are subsequently targeted for ubiquitylation and rapid proteolysis, which is expected to generate 5'-peptidyl-dL-DNA adducts. Inhibition of theproteasome prevents removal of Pol beta-DPC (3B), leading to their toxic accumulation with cell killing and perhaps other consequences. Mitochondrial DNA polymerase gamma (Pol gamma), which harbors a 5'-dRp lyase similar to that of Pol beta, is also trapped by 5'-dL
malfunction
three Pol beta enzymes modified at position 72 with aminooxy or hydrazinyl analogues of lysine form transient covalent bonds with the 5'-dRP moiety of the damaged DNA, in the form of an oxime or hydrazone, respectively. Both types of enzyme DNA intermediates are ultimately resolved by the lyase activities of each of the modified enzymes. The formation and resolution of these E-S complexes proceed with diminished kinetics, and with an altered pH profile compared to wild-type. Comparison of base excision repair (BER) reaction with wild-type and modified Pol beta enzymes: while the wild-type enzyme performs BER very efficiently, the BER activity of the three modified enzymes is greatly reduced. The overall BER efficiency of our modified Pol beta enzymes reflects predominantly their ability to remove the 5'-dRP group, the modified proteins demonstrate poor lyase activity
physiological function
isoform POLB expression rescues methyl methanesulfonate sensitivity in aprataxin (hnt3)- and FEN1 (rad27)-deficient yeast. Model suggests that aprataxin hydrolyzes the 5'-AMP group and allows for renewed attempts at processing of the repair intermediate, and the 5'-deoxyribose phosphate may be channeled into the normal base excision repair pathway for isoform POLB deoxyribose phsosphate removal and gap filling. In long-path base excision repair, the blocking intermediates can be processed via flap excision by FEN1. In an alternative mechanism, POLB could play a part by direct removal of the entire 5'-AMP-deoxyribose phosphate blocking group via its deoxyribose phosphate lyase activity
physiological function
DNA polymerase beta (Pol beta) is a key enzyme in mammalian base excision repair (BER), contributing stepwise 5'-deoxyribose phosphate (dRP) lyase and gap-filling DNA polymerase activities. The lyase reaction is believed to occur via a beta-elimination reaction following the formation of a Schiff base between the dRP group at the pre-incised apurinic/apyrimidinic site and the epsilon-amino group of Lys72
physiological function
DNA polymerase beta (Pol beta) participates in mammalian base excision repair (BER). The enzyme has a two-domain architecture, reflecting its dual functionality. The polymerase activity, which replaces damaged nucleosides removed during an initial excision process, is within the C-terminal 31 kDa domain, while the N-terminal 8 kDa domain participates in a lyase function, working to remove a 5'-deoxyribose phosphate (5'-dRP) moiety from the damaged DNA substrate
physiological function
DNA polymerase beta (PolB) has both DNA polymerase and dRP lyase activities. Enzyme PolB plays a dominant role in single nucleotide (Sn-) BER by incorporating a nucleotide and removing 5'-dRp. Methyl methanesulfonate (MMS)-induced damage is repaired by Sn-BER
physiological function
oxidized abasic sites are initially incised by Ape1, thus recruiting these lesions into base excision repair (BER) pathways. Lesions such as 2-deoxypentos-4-ulose can be removed by conventional (single-nucleotide) BER, which proceeds through a covalent Schiff base intermediate with DNA polymerase beta (Pol beta) that is resolved by hydrolysis. In contrast, the lesion 2-deoxyribonolactone (dL) must be processed by multinucleotide (long-patch) BER: attempted repair via the single-nucleotide pathway leads to a dead-end, covalent complex with Pol beta cross-linked to the DNA by an amide bond. In classical base excision repair (BER), only the missing nucleotide is replaced by DNA polymerase beta (Pol beta), and the deoxyribose-5'-phosphate (5'-dRp) residue is excised by a 5'-dRp lyase activity in a discrete domain of Pol beta. The result is a nicked DNA that is competent for ligation, usually by DNA ligase III alpha. Another subpathway called long-patch BER (LP-BER) also exists, in which DNA repair synthesis replaces 2-10 nucleotides, Fen1 (flap) endonuclease excises the displaced strand, and DNA ligase I seals the nick. LP-BER repair synthesis can be initiated by Pol beta, which may (inefficiently) insert a second nucleotide. When the 5'-dRp strand is displaced by two or more nucleotides, the 5'-dRp lyase of Pol beta no longer functions, requiring Fen1 to remove the single-stranded flap. BER processing of oxidative DNA damage and the formation of DNA-protein crosslinks (DPC), overview
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E71Q
retains wild-type enzyme activity
E75A
about 75% of wild-type enzyme activity
F25W
about 85% of wild-type enzyme activity
H34G
about 45% of wild-type enzyme activity
K35A/K68A
part of the active site, similar to wild-type enzyme activity
K35A/K72A
part of the active site, above 95% loss of enzyme activity
K35R
part of the active site, no effect on enzyme activity
K35R/K68R/K72R
part of the active site, above 95% loss of enzyme activity
K60A
about 40% of wild-type enzyme activity
K68A/E71Q
retains wild-type enzyme activity
K68A/K72A
about 10% of wild-type enzyme activity
K68R
part of the active site, significant reduction of enzyme activity
K72R
part of the active site, above 95% loss of enzyme activity
K84A
retains wild-type enzyme activity
Y39F
part of the active site, similar to wild-type enzyme activity
D829N/E830Q
-
the polymerase inactive mutant D829N/E830Q retains full 5'-dRP lyase activity. Domain mapping of the 98-kDa enzyme reveals that the 5'-dRP lyase active site resides in a 24-kDa-domain
K310A
eliminates more than 90% of the wild-type dRP lyase activity, indicating that Lys 310 is the main nucleophile involved in the reaction, forming the Schiff base internediate during beta-elimination
additional information
the lyase catalytic pocket, Lys72, is replaced with each of several nonproteinogenic lysine analogues. The modified Pol beta enzymes are produced by coupled in vitro transcription and translation from a modified DNA template containing a TAG codon at the position corresponding to Lys72. In the presence of a misacylated tRNACUA transcript, suppression of the UAG codon in the transcribed mRNA leads to elaboration of full-length Pol beta having a lysine analogue at position 72. Replacement of the primary nucleophilic amine with a secondary amine in the form of N-methyllysine affects mainly the stability of the Schiff base intermediate and results in relatively moderate inhibition of lyase activity and BER. Elongation of the side chain of the catalytic residue by one methylene group, achieved by introduction of homolysine at position 72, apparently shifts the amino group to a position less favorable for Schiff base formation. This effect is attenuated when the side chain is elongated by replacing one side-chain methylene group with a bridging S atom (thialysine). In comparison, replacement of lysine 72 with an analogue having a guanidine moiety in lieu of an epsilon-amino group (homoarginine) or a sterically constrained secondary amine (piperidinylalanine) leads to almost complete suppression of dRP excision activity and the ability of Pol beta to support BER
K35A
about 50% of wild-type enzyme activity, Lys72 and Lys35 are involved in the dRP lyase reaction catalyzed by the 8-kDa domain and Lys35 is involved in 5'-phosphate recognition. Lys35 may stabilize the leaving group in the dRP lyase reaction through its interaction with the 5'-phosphate of the DNA-terminus
K35A
part of the active site, 50% loss of enzyme activity
K35A/K68A/K72A
devoid of dRP lyase, Lys72 and Lys35 are involved in the dRP lyase reaction catalyzed by the 8-kDa domain and Lys35 is involved in 5'-phosphate recognition. Lys35 may stabilize the leaving group in the dRP lyase reaction through its interaction with the 5'-phosphate of the DNA-terminus
K35A/K68A/K72A
part of the active site, above 95% loss of enzyme activity
K68A
part of the active site, stimulation of enzyme activity
K68A
retains wild-type enzyme activity
K68A
mutation has no significant effect on the removal of 5'-AMP-deoxyribose phosphate
K72A
less than 10% of wild-type enzyme activity, Lys72 and Lys35 are involved in the dRP lyase reaction catalyzed by the 8-kDa domain and Lys35 is involved in 5'-phosphate recognition. Lys35 may stabilize the leaving group in the dRP lyase reaction through its interaction with the 5'-phosphate of the DNA-terminus
K72A
part of the active site, above 95% loss of enzyme activity
K72A
-
2 mM pyridoxal 5'-phosphate, the mutant K72A of the 8-kDa domain and the full-lenghth protein beta-pol exhibit 90 and 80% loss of activity, respectively
K72A
-
mutant is not able to exhibit short-patch repair mechanism
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Prasad, R.; Batra, V.K.; Yang, X.P.; Krahn, J.M.; Pedersen, L.C.; Beard, W.A.; Wilson, S.H.
Structural insight into the DNA polymerase beta deoxyribose phosphate lyase mechanism
DNA Repair
4
1347-1357
2005
Homo sapiens (P06746)
brenda
Allinson, S.L.; Dianova, II; Dianov, G.L.
DNA polymerase beta is the major dRP lyase involved in repair of oxidative base lesions in DNA by mammalian cell extracts
EMBO J.
20
6919-6926
2001
Homo sapiens
brenda
Prasad, R.; Beard, W.A.; Chyan, J.Y.; Maciejewski, M.W.; Mullen, G.P.; Wilson, S.H.
Functional analysis of the amino-terminal 8-kDa domain of DNA polymerase beta as revealed by site-directed mutagenesis. DNA binding and 5'-deoxyribose phosphate lyase activities
J. Biol. Chem.
273
11121-11126
1998
Homo sapiens (P06746)
brenda
Prasad, R.; Beard, W.A.; Strauss, P.R.; Wilson, S.H.
Human DNA polymerase beta deoxyribose phosphate lyase. Substrate specificity and catalytic mechanism
J. Biol. Chem.
273
15263-15270
1998
Homo sapiens
brenda
Garcia-Diaz, M.; Bebenek, K.; Kunkel, T.A.; Blanco, L.
Identification of an intrinsic 5'-deoxyribose-5-phosphate lyase activity in human DNA polynmerase lambda. A possible role in base excision repair
J. Biol. Chem.
276
34659-34663
2001
Homo sapiens (Q9UGP5), Homo sapiens
brenda
Wong, D.; Demple, B.
Modulation of the 5'-deoxyribose-5-phosphate lyase and DNA synthesis activities of mammalian DNA polymerase beta by apurinic/apyrimidinic endonuclease 1
J. Biol. Chem.
279
25268-25275
2004
Homo sapiens
brenda
Prasad, R.; Longley, M.J.; Sharief, F.S.; Hou, E.W.; Copeland, W.C.; Wilson, S.H.
Human DNA polymerase theta possesses 5'-dRP lyase activity and functions in single-nucleotide base excision repair in vitro
Nucleic Acids Res.
37
1868-1877
2009
Homo sapiens
brenda
Longley, M.J.; Prasad, R.; Srivastava, D.K.; Wilson, S.H.; Copeland, W.C.
identification of 5'-deoxyribose phosphate lyase activity in human DNA polymerase gamma and its role in mitochondrial base excision repair in vitro
Proc. Natl. Acad. Sci. USA
95
12244-12248
1998
Homo sapiens
brenda
Bebenek, K.; Tissier, A.; Frank, E.G.; McDonald, J.P.; Prasad, R.; Wilson, S.H.; Woodgate, R.; Kunkel, T.A.
5'-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro
Science
291
2156-2159
2001
Homo sapiens
brenda
Caglayan, M.; Batra, V.K.; Sassa, A.; Prasad, R.; Wilson, S.H.
Role of polymerase beta in complementing aprataxin deficiency during abasic-site base excision repair
Nat. Struct. Mol. Biol.
21
497-499
2014
Homo sapiens (P06746)
brenda
Daskalova, S.M.; Bhattacharya, C.; Dedkova, L.M.; Hecht, S.M.
Probing the flexibility of the catalytic nucleophile in the lyase catalytic pocket of human DNA polymerase beta with unnatural lysine analogues
Biochemistry
56
500-513
2017
Homo sapiens (P06746)
brenda
Daskalova, S.M.; Bai, X.; Hecht, S.M.
Study of the lyase activity of human DNA polymerase beta using analogues of the intermediate Schiff base complex
Biochemistry
57
2711-2722
2018
Homo sapiens (P06746)
brenda
Quinones, J.L.; Demple, B.
When DNA repair goes wrong BER-generated DNA-protein crosslinks to oxidative lesions
DNA Repair
44
103-109
2016
Homo sapiens (P06746)
brenda
Yamamoto, R.; Umetsu, M.; Yamamoto, M.; Matsuyama, S.; Takenaka, S.; Ide, H.; Kubo, K.
AP endonuclease knockdown enhances methyl methanesulfonate hypersensitivity of DNA polymerase beta knockout mouse embryonic fibroblasts
J. Radiat. Res.
56
462-466
2015
Homo sapiens (P06746), Mus musculus (Q8K409)
brenda