Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
adenosine 5'-phosphoramidate + H2O
?
13% of the activity with adenosine 5'-phosphosulfate
-
-
?
adenosine 5'-phosphosulfate + H2O
?
-
-
-
?
adenosine-5'-diphospho-5'-(ribonucleotide)-[DNA] + H2O
AMP + 5'-phospho-(ribonucleotide)-[DNA]
adenosine-5'-diphospho-5'-[5'-AGATTATCTTCGAGCTAC-3'] + H2O
AMP + phospho-5'-[5'-AGATTATCTTCGAGCTAC-3']
-
-
-
?
adenosine-5'-diphospho-5'-[5'-ATTCCGATAGTGACTACA-3'] + H2O
AMP + phospho-5'-[5'-ATTCCGATAGTGACTACA-3']
-
-
-
?
adenosine-5'-diphospho-5'-[5'-CATATCCGTGTCGCCCTCATTCCGATAGTGACTACA-3'] + H2O
AMP + phospho-5'-[5'-CATATCCGTGTCGCCCTCATTCCGATAGTGACTACA-3']
-
-
-
?
adenosine-5'-diphospho-5'-[5'-GTAGCTCGAAGATAATCTGAGGGCGACACGGATATG-3'] + H2O
AMP + phospho-5'-[5'-GTAGCTCGAAGATAATCTGAGGGCGACACGGATATG-3']
-
-
-
?
adenosine-5'-diphospho-5'-[5'-TGTAGTCACTATCGGAATGAGGGCGACACGGATATG-3'] + H2O
AMP + phospho-5'-[5'-TGTAGTCACTATCGGAATGAGGGCGACACGGATATG-3']
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
adenosine-5'-monophosphoramidate + H2O
AMP + NH3
-
-
-
?
ATP + H2O
AMP + diphosphate
-
-
-
?
P1,P3-bis(5'-adenosyl)triphosphate + H2O
AMP + ADP
-
-
-
?
P1,P4-bis(5'-adenosyl)tetraphosphate + H2O
?
-
-
-
?
P1,P4-bis(5'-adenosyl)tetraphosphate + H2O
AMP + ATP
-
-
-
?
additional information
?
-
adenosine-5'-diphospho-5'-(ribonucleotide)-[DNA] + H2O
AMP + 5'-phospho-(ribonucleotide)-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-(ribonucleotide)-[DNA] + H2O
AMP + 5'-phospho-(ribonucleotide)-[DNA]
-
-
-
-
?
adenosine-5'-diphospho-5'-(ribonucleotide)-[DNA] + H2O
AMP + 5'-phospho-(ribonucleotide)-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-(ribonucleotide)-[DNA] + H2O
AMP + 5'-phospho-(ribonucleotide)-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
substrate with single strand DNA
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
the enzyme can use nicked and blunt substrates
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
substrate with single strand DNA
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
substrate with single strand DNA
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
adenosine-5'-diphospho-5'-[DNA] + H2O
AMP + phospho-5'-[DNA]
-
-
-
?
additional information
?
-
aprataxin resolves abortive DNA ligation intermediates. Aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5'-phosphate termini at single-strand nicks and gaps, resulting in the production of 5'-phosphate termini that can be efficiently rejoined
-
-
?
additional information
?
-
-
aprataxin resolves abortive DNA ligation intermediates. Aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5'-phosphate termini at single-strand nicks and gaps, resulting in the production of 5'-phosphate termini that can be efficiently rejoined
-
-
?
additional information
?
-
substrate binding structure, overview
-
-
?
additional information
?
-
-
substrate binding structure, overview
-
-
?
additional information
?
-
aprataxin hydrolyzes with similar efficiency the model histidine triad nucleotide-binding protein substrate : adenosine-5'-monophosphoramidate, AMPNH2, and the Fragile histidine triad protein substrate, Ap4A. No substrate: dATP
-
-
?
additional information
?
-
aprataxin possesses an active-site-dependent AMP-lysine and GMP-lysine hydrolase activity that depends additionally on the zinc finger for protein stability and on the forkhead associated domain for enzymatic activity. Aprataxin also shows guanosine-5'-diphospho-5'-[DNA] diphosphatase activity, reaction of EC 3.1.11.8
-
-
?
additional information
?
-
aprataxin hydrolyses abnormal 5'-AMP DNA termini formed in abortive DNA ligations
-
-
?
additional information
?
-
APTX-mediated DNA deadenylation activity (i.e. 5'-AMP removal) is measured in extracts of cells expressing wild-type XRCC1 or the XRCC1 phosphorylation mutant, and compared with activity in APTX-deficient and APTX-complemented human cells. APTX activity is lower in extracts from Xrcc1-/- and XRCC1 phosphorylation mutant cells compared to the robust activity in extract from wild-type XRCC1 expressing cells. And APTX-mediated DNA deadenylation activity (i.e. 5'-AMP removal) is measured in cell extracts of the XRCC1 variants, and compared with activity in patient AOA1 human fibroblasts and APTX-complemented cells
-
-
?
additional information
?
-
APTX-mediated DNA deadenylation activity (i.e. 5'-AMP removal) is measured
-
-
?
additional information
?
-
aprataxin acts preferentially on adenylated nicks and double-strand breaks rather than on single-stranded DNA
-
-
?
additional information
?
-
the target of APTX ares 5'-adenylates at DNA nicks or breaks that result from abortive DNA ligation reactions
-
-
?
additional information
?
-
-
the target of APTX ares 5'-adenylates at DNA nicks or breaks that result from abortive DNA ligation reactions
-
-
?
additional information
?
-
aprataxin resolves abortive DNA ligation intermediates. Aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5'-phosphate termini at single-strand nicks and gaps, resulting in the production of 5'-phosphate termini that can be efficiently rejoined
-
-
?
additional information
?
-
-
aprataxin resolves abortive DNA ligation intermediates. Aprataxin catalyses the nucleophilic release of adenylate groups covalently linked to 5'-phosphate termini at single-strand nicks and gaps, resulting in the production of 5'-phosphate termini that can be efficiently rejoined
-
-
?
additional information
?
-
aprataxin additionally is a DNA 3'-de-capping enzyme, converting DNAppG to DNA3'p and GMP, reaction of EC 3.1.12.2. Aprataxin hydrolyzes inosine and 6-O-methylguanosine caps, but not adeoxyguanosine cap
-
-
?
additional information
?
-
mechanism involves nucleophilic attack of DNA 5'-adenylate by His147 to generate a covalent enzyme-AMP intermediate. His147 is stabilized by a close hydrogen bond with the Asn145 main chain carbonyl. The Aptx-specific His168-Ser168 pair appears positioned to activate solvent for hydrolysis of the enzyme-AMP intermediate. His168 may also act as a proton donor to the bridging oxygen in the first step
-
-
?
additional information
?
-
-
mechanism involves nucleophilic attack of DNA 5'-adenylate by His147 to generate a covalent enzyme-AMP intermediate. His147 is stabilized by a close hydrogen bond with the Asn145 main chain carbonyl. The Aptx-specific His168-Ser168 pair appears positioned to activate solvent for hydrolysis of the enzyme-AMP intermediate. His168 may also act as a proton donor to the bridging oxygen in the first step
-
-
?
additional information
?
-
mechanism involves nucleophilic attack of DNA 5'-adenylate by His147 to generate a covalent enzyme-AMP intermediate. His147 is stabilized by a close hydrogen bond with the Asn145 main chain carbonyl. The Aptx-specific His168-Ser168 pair appears positioned to activate solvent for hydrolysis of the enzyme-AMP intermediate. His168 may also act as a proton donor to the bridging oxygen in the first step
-
-
?
additional information
?
-
aprataxin additionally is a DNA 3'-de-capping enzyme, converting DNAppG to DNA3'p and GMP, reaction of EC 3.1.12.2. Aprataxin hydrolyzes inosine and 6-O-methylguanosine caps, but not adeoxyguanosine cap
-
-
?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
evolution
aprataxin (APTX) belongs to a family of histidine triad (HIT) enzymes. Mutation of His138 to alanine does not completely abolish the catalytic activity; the residual activity is 25% of the wild-type enzyme activity. The DNA deadenylation reaction catalyzed by the H138A mutant can proceed by the protonated substrate
malfunction
APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). AOA1 mutagenic effects on APTX solubility, stability, and catalytic activity, and molecular basis for APTX inactivation in AOA1, APTX mutations variably impact protein folding and activity, overview
malfunction
ataxia oculomotor apraxia-1 (AOA1) is a recessive human neurodegenerative disorder linked to more than 20 distinct mutations in the gene encoding APTX. Although reminiscent of ataxia-telangiectasia, primary AOA1 fibroblasts exhibit only mild hypersensitivity to ionizing radiation
malfunction
lack of aprataxin impairs mitochondrial functions, independent of its role in mitochondrial DNA repair, via downregulation of the APE1/NRF1/NRF2 pathway. Ataxia oculomotor apraxia type 1 (AOA1) is an autosomal recessive disease caused by mutations in APTX, which encodes the DNA strand-break repair protein aprataxin (APTX). CoQ10 deficiency is identified in fibroblasts and muscle of AOA1 patients carrying the common W279X mutation, and aprataxin has been localized to mitochondria in neuroblastoma cells, where it enhances preservation of mitochondrial function. The bioenergetics defect in AOA1-mutant fibroblasts and APTX-depleted Hela cells is caused by decreased expression of SDHA and genes encoding CoQ biosynthetic enzymes, in association with reductions of APE1, NRF1 and NRF2. APE1 depletion impairs NRF1 expression in Hela cells and resembles APTX knockdown clones, mitochondrial genes are downregulated in APE1-deficient cells owing to the regulatory role of APE1 on DNA-binding and transcriptional activity of NRF1
malfunction
mutation of aprataxin (APTX) is causing the heritable neurological disorder ataxia with oculomotor apraxia 1 (AOA1)
malfunction
mutations of the APTX gene cause neurological diseases such as ataxia oculomotor aparaxia type 1 (AOA1)
malfunction
while hnt3DELTA single mutants are not sensitive to DNA damaging agents, loss of HNT3 causes synergistic sensitivity to H2O2 in backgrounds that accumulate strand breaks with blocked termini, including apn1DELTA/apn2DELTA/tpp1DELTA and ntg1DELTA/ntg2DELTA/ogg1DELTA. Loss of HNT3 in rad27DELTA cells, which are deficient in long-patch base excision repair (LP-BER), results in synergistic sensitivity to H2O2 and methylmethane sulfonate, indicating that Hnt3 and LP-BER provide parallel pathways for processing 5'-AMPs. Loss of HNT3 also increases the sister chromatid exchange frequency. HNT3 deletion partially rescues H2O2 sensitivity in recombination deficient rad51DELTA and rad52DELTA cells, suggesting that Hnt3 promotes formation of a repair intermediate that is resolved by recombination. Expression of Myc-NLS-tagged human aprataxin from a plasmid complements HNT3 deletion
physiological function
aprataxin has dual DNA binding and nucleotide hydrolase activities. The protein binds to double-stranded DNA with high affinity but is also capable of binding double-stranded RNA and single-strand DNA, with increased affinity for hairpin structures. The DNA binding is not dependent on zinc
physiological function
aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and colocalizes with XRCC1 along charged particle tracks on chromatin
physiological function
FLJ20157
aprataxin is directly involved in DNA single-strand-break repair
physiological function
aprataxin localizes at sites of DNA damage induced by high low linear energy transfer radiation and binds to mediator of DNA-damage checkpoint protein MDC1/NFBD1 through a phosphorylation-dependent interaction. This interaction is mediated via the aprataxin forkhead-associated domain and multiple casein kinase 2 diphosphorylated S-D-T-D motifs in MDC1
physiological function
APTX interacts with X-ray repair cross-complementing group XRCC1, which has an essential role in single-strand DNA break repair. The 20 N-terminal amino acids of the forkhead-associated FHA-domain of APTX are important for its interaction with the C-terminal region (residues 492574) of XRCC1. Poly(ADPribose) polymerase PARP-1 is also co-immunoprecipitated with APTX
physiological function
-
deletion of the Saccharomyces cerevisiae Hnt3 gene, which encodes the aprataxin homolog, in combination with known DNA repair genes. While Hnt3 single mutants are not sensitive to DNA damaging agents, loss of Hnt3 causes synergistic sensitivity to H2O2 in backgrounds that accumulate strand breaks with blocked termini, including lack of Apn1, Apn2, Tpp1 and Ntg1, Ntg2, Ogg1. Loss of HNT3 in Rad27 mutant cells, which are deficient in long-patch base excision repair, results in synergistic sensitivity to H2O2 and methylmethane sulfonate. Loss of Hnt3 also increases the sister chromatid exchange frequency. Hnt3 deletion partially rescues H2O2 sensitivity in recombination-deficient mutant Rad51 and mutant Rad52 cells
physiological function
during repair of non-canonical ribonucleotides introduced into DNA during replication of the nuclear genome, DNA ligases generate 5'-adenylated RNA-DNA junctions repaired by Aptx deadenylase. In the proposed reaction scheme, step 1 generates an enzyme-AMP intermediate, which is then resolved via hydrolysis
physiological function
interaction between aprataxin and nucleolin occurs through their respective N-terminal regions. In cells from patients with ataxia with oculomotor apraxia type 1, AOA1, lacking aprataxin, the stability of nucleolin is significantly reduced. Down-regulation of nucleolin by RNA interference does not affect aprataxin protein levels but abolishes its nucleolar localization
physiological function
ligases generate adenylated 5'-ends containing a ribose characteristic of RNaseH2 incision. Aptx efficiently repairs adenylated RNA-DNA, and acting in an RNA-DNA damage response, promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RNaseH2-dependent excision repair
physiological function
poly-ADP ribose polymerase PARP-1 is required in the recruitment of aprataxin to sites of DNA breaks. Inhibition of PARP activity does not affect aprataxin activity in vitro, it retards its recruitment to sites of DNA damage in vivo
physiological function
the long-form but not the short-form aprataxin interacts with x-ray repair cross-complementing group XRCC1. Aprataxin and XRCC1 may constitute a multiprotein complex and are involved in single-strand DNA break repair
physiological function
the protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'-phosphatase, with histidine-triad proteins and with DNA-binding C2H2 zinc-finger proteins, respectively
physiological function
5'-AMP DNA hydrolysis of aprataxin, energy profile of the APTX catalytic reaction and the protonate states, by quantum mechanical/molecular mechanical (QM/MM) calculations and modeling, overview. Aprataxin hydrolyses abnormal 5'-AMP DNA termini formed in abortive DNA ligations, it is an important DNA repair enzyme
physiological function
aprataxin (APTX) is a DNA-adenylate hydrolase that removes 5'-AMP blocking groups from abortive ligation repair intermediates. Primary role of aprataxin is processing of adenylated 5' ends. XRCC1, a multi-domain protein without catalytic activity, interacts with a number of known repair proteins including APTX, modulating and coordinating the various steps of DNA repair. CK2- phosphorylation of XRCC1 is thought to be crucial for its interaction with the FHA domain of APTX. A phosphorylated XRCC1 is required for APTX recruitment.No interaction of APTX with a phosphorylation mutant of XRCC1
physiological function
critical role of APTX in transcription regulation of mitochondrial function and the pathogenesis of AOA1 via a novel pathomechanistic pathway, which may be relevant to other neurodegenerative diseases
physiological function
eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions create 5'-adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA base excision repair (BER), double strand break repair (DSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder ataxia with oculomotor apraxia 1 (AOA1), acts as a DNA ligase proofreader to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage response, molecular mechanism, overview. Elongation of the wedge helix enables dynamic interactions with both the AMP lesion and the exposed base stack on the 5'-end of the damaged DNA strand. The second major DNA binding interface involves undamaged DNA strand binding by the Znf domain
physiological function
Hnt3 promotes formation of a repair intermediate that is resolved by recombination. Hnt3 and LP-BER provide parallel pathways for processing 5'-AMPs, and Hnt3 promotes formation of a repair intermediate that is resolved by recombination. Lack of evidence for Hnt3 involvement in nonhomologous end joining
physiological function
the APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease, mechanism
physiological function
APTX acts as a nick sensor. When an adenylated nick is encountered by APTX, base pairing at the 5' terminus of the nick is disrupted as the adenylate is accepted into the active site of the enzyme. Adenylate removal occurs by a two-step process that proceeds through a transient AMP-APTX covalent intermediate
physiological function
-
APTX suppresses DNA-ligase 11-catalyzed ligation of 8oxoG-containing DNA. In presence of APTX, the catalytic commitment of DNA ligase 1 to erroneous ligation is reduced by 70 and 90%, respectively, for the 8oxoG:A and 8oxoG:C substrates
physiological function
depletion of aprataxin in human SHSY5Y neuroblastoma cells and primary skeletal muscle myoblasts results in mitochondrial dysfunction, revealed by reduced citrate synthase activity and mtDNA copy number. mtDNA, not nuclear DNA, has higher levels of background DNA damage on aprataxin knockdown
physiological function
FD105 cells, lacking aprataxin, show a 5.7-fold increase in diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) level
physiological function
knockdown of aprataxin expression in EM-9 cells leads to an 8fold increase in Ap4A level to 31.4 pmol/106 cells. APTX knockdown greatly enhances the mitomycin C-induced Ap4A increase in AA-8 cells from 3.9 to 10.6 pmol/106 cells
physiological function
the catalytic activity of Aptx resides within the HIT domain, the C-terminal zinc finger domain provides stabilizing contacts that lock the enzyme onto its high affinity AMP-DNA target site. Both domains are required for efficient AMP-DNA hydrolase activity. Aprataxin plays a role in base excision repair, specifically in the removal of adenylates that arise from abortive ligation reactions that take place at incised abasic sites in DNA
physiological function
-
ligases generate adenylated 5'-ends containing a ribose characteristic of RNaseH2 incision. Aptx efficiently repairs adenylated RNA-DNA, and acting in an RNA-DNA damage response, promotes cellular survival and prevents S-phase checkpoint activation in budding yeast undergoing RNaseH2-dependent excision repair
-
additional information
active site structure of APTX, and molecular reaction mechanism, modeling, overview. General acid-base catalysis of APTX with and important role of His138 as a general acid. The second step, the histidine-AMP intermediate hydrolysis, can proceed with the aid of the product DNA phosphate without a general base residue
additional information
two highly conserved amino acid sequence motifs typify the HIT-Znf region of APTX. The first is the histidine triad motif HXHXHXX (X = hydrophobic residue) of the HIT domain, and the second is a C-terminal Zn-binding (Znf) domain with a sequence motif C(x2)C(x11-12)H(x3)H/E (x = any amino acid). This core HIT-Znf architecture is conserved in APTX orthologs with bona-fide polynucleotide adenylate hydrolase activity including plant, yeast and vertebrate homologues, suggesting that the Znf domain imparts critical substrate specificity to the aprataxins. The APTX Zn2+-binding betabetaalpha core is structurally related to the ubiquitous family of DNA binding C2H2 transcription factors including the prototypical Zif268. APTX Zn2+ ligands can be of either the C2H2 (Cys2-His2 in vertebrate APTX) or C2HE (Cys2-His-Glu in fungal Aptx), which both fold into very similar DNA damage recognition elements
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
689insT
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
840delT
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
A198V/P206L
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
D267G/W279X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
G231E/689insT
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
H138A
site-directed mutagenesis, mutation of His138 to alanine does not completely abolish the catalytic activity, the residual activity is 25% of the wild-type enzyme activity. The DNA deadenylation reaction catalyzed by the H138A mutant can proceed by the protonated substrate
H201A
mutant displays weak activity
H258A
mutant displays substantial residual activity
H260N
-
catalytically inactive
H262A
mutant displays weak activity
K197Q/W279X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
R29A
mutation of forkhead-associated domain residue, prevents its interaction with mediator of DNA-damage checkpoint protein MDC1 and recruitment to sites of DNA damage
R306X/W279X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
S242N
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
T739C
FLJ20157
homozygous mutation idientified in a patient with ataxia-oculomotor apraxia type 1
V263G/P206L
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
W279R/IVS5
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
W279X/I159fs
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
W279X/Q181X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
W279X/R306X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
H138A
mutation significantly impairs deadenylation activity
H147N
complete loss of activity
S168A
mutation significantly impairs deadenylation activity
H138A
-
mutation significantly impairs deadenylation activity
-
H147N
-
complete loss of activity
-
S168A
-
mutation significantly impairs deadenylation activity
-
A198V
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
A198V
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
A198V
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
D185E
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX
D185E
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
D267G
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
D267G
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
D267G
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
G231E
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
G231E
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
H201Q
naturally occuring active site mutation, the mutant displays impaired AMP-lysine hydrolase activity
H201Q
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
H201R
naturally occuring active site mutation, the mutant displays impaired AMP-lysine hydrolase activity
H201R
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
H260A
no detectable activity
H260A
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
K197Q
mutation identified in patient with AOA1. The mutant protein harbors a distorted active site pocket
K197Q
recessive mutation associated with ataxia but not oculomotor apraxia, mild presentation allele
K197Q
naturally occuring mutation, the mutant displays impaired AMP-lysine hydrolase activity, confers a late onset neurological disease AOA1
K197Q
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
L223P
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
L223P
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
L248M
naturally occuring dominant mutation in APTX
L248M
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
P206L
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
P206L
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
R199H
recessive mutation associated with ataxia and oculomotor apraxia, protein retains substantial function, consistent with altered activity
R199H
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
R247X
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
R247X
site-directed mutagenesis, not involved in AOA1 disease
R306X
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
R306X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
V263G
mutation identified in a AOA1 patient, mutant protein is unable to bind DNA
V263G
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
V263G
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant
V263G
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
W279R
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
W279R
naturally occuring mutation, the mutant displays impaired AMP-lysine hydrolase activity, confers a late onset neurological disease AOA1
W279R
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
W279X
recessive mutation associated with ataxia and oculomotor apraxia, huge loss in protein stability
W279X
naturally occuring mutation causing Ataxia oculomotor apraxia type 1 (AOA1) autosomal recessive disease
W279X
naturally occuring mutation predicted to affect protein stability by destabilizing or truncating the folded core of APTX, catalytically inactive mutant, confers a late onset neurological disease AOA1
W279X
site-directed mutagenesis, a mutation causing the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1)
additional information
removal of the N-terminal forkhead associated domain does not alter activity with substrates AMPNH2 and Ap4A
additional information
the biochemical and molecular abnormalities in APTX-depleted cells are recapitulated by knockdown of APE1 in Hela cells and are rescued by overexpression of NRF1/2. Importantly, pharmacological upregulation of NRF1 alone by 5-aminoimidazone-4-carboxamide ribonucleotide does not rescue the phenotype, which, in contrast, is reversed by the upregulation of NRF2 by rosiglitazone. The lack of aprataxin causes reduction of the pathway APE1/NRF1/NRF2 and their target genes. APTX-mutant fibroblasts show reduced succinate dehydrogenase. APTX-mutant fibroblasts show reduced levels and biosynthesis of CoQ10. Levels of APE1 are reduced in APTX-mutant and APTX-depleted cells. Phenotype, overview
additional information
-
the biochemical and molecular abnormalities in APTX-depleted cells are recapitulated by knockdown of APE1 in Hela cells and are rescued by overexpression of NRF1/2. Importantly, pharmacological upregulation of NRF1 alone by 5-aminoimidazone-4-carboxamide ribonucleotide does not rescue the phenotype, which, in contrast, is reversed by the upregulation of NRF2 by rosiglitazone. The lack of aprataxin causes reduction of the pathway APE1/NRF1/NRF2 and their target genes. APTX-mutant fibroblasts show reduced succinate dehydrogenase. APTX-mutant fibroblasts show reduced levels and biosynthesis of CoQ10. Levels of APE1 are reduced in APTX-mutant and APTX-depleted cells. Phenotype, overview
additional information
construction of hnt3DELTA single mutants and HNT3 knockout mutants, including apn1DELTA/apn2DELTA/tpp1DELTA and ntg1DELTA/ntg2DELTA/ogg1DELTA. Loss of HNT3 in rad27DELTA cells, which are deficient in long-patch base excision repair (LP-BER), results in synergistic sensitivity to H2O2 and methylmethane sulfonate. HNT3 deletion partially rescues H2O2 sensitivity in recombination deficient rad51DELTA and rad52DELTA cells. Hnt3 point mutations and complementation with human aprataxin. Phenotypes, overview
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
Harris, J.L.; Jakob, B.; Taucher-Scholz, G.; Dianov, G.L.; Becherel, O.J.; Lavin, M.F.
Aprataxin, poly-ADP ribose polymerase 1 (PARP-1) and apurinic endonuclease 1 (APE1) function together to protect the genome against oxidative damage
Hum. Mol. Genet.
18
4102-4117
2009
Homo sapiens (Q7Z2E3)
brenda
Sano, Y.; Date, H.; Igarashi, S.; Onodera, O.; Oyake, M.; Takahashi, T.; Hayashi, S.; Morimatsu, M.; Takahashi, H.; Makifuchi, T.; Fukuhara, N.; Tsuji, S.
Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein
Ann. Neurol.
55
241-249
2004
Homo sapiens (Q7Z2E3)
brenda
Date, H.; Igarashi, S.; Sano, Y.; Takahashi, T.; Takahashi, T.; Takano, H.; Tsuji, S.; Nishizawa, M.; Onodera, O.
The FHA domain of aprataxin interacts with the C-terminal region of XRCC1
Biochem. Biophys. Res. Commun.
325
1279-1285
2004
Homo sapiens (Q7Z2E3)
brenda
Mosesso, P.; Piane, M.; Palitti, F.; Pepe, G.; Penna, S.; Chessa, L.
The novel human gene aprataxin is directly involved in DNA single-strand-break repair
Cell. Mol. Life Sci.
62
485-491
2005
Homo sapiens (FLJ20157), Homo sapiens
brenda
Daley, J.M.; Wilson, T.E.; Ramotar, D.
Genetic interactions between HNT3/aprataxin and RAD27/FEN1 suggest parallel pathways for 5' end processing during base excision repair
DNA Repair
9
690-699
2010
Saccharomyces cerevisiae
brenda
Gueven, N.; Becherel, O.J.; Kijas, A.W.; Chen, P.; Howe, O.; Rudolph, J.H.; Gatti, R.; Date, H.; Onodera, O.; Taucher-Scholz, G.; Lavin, M.F.
Aprataxin, a novel protein that protects against genotoxic stress
Hum. Mol. Genet.
13
1081-1093
2004
Homo sapiens (Q7Z2E3), Homo sapiens
brenda
Becherel, O.J.; Gueven, N.; Birrell, G.W.; Schreiber, V.; Suraweera, A.; Jakob, B.; Taucher-Scholz, G.; Lavin, M.F.
Nucleolar localization of aprataxin is dependent on interaction with nucleolin and on active ribosomal DNA transcription
Hum. Mol. Genet.
15
2239-2249
2006
Homo sapiens (Q7Z2E3), Homo sapiens
brenda
Seidle, H.F.; Bieganowski, P.; Brenner, C.
Disease-associated mutations inactivate AMP-lysine hydrolase activity of aprataxin
J. Biol. Chem.
280
20927-20931
2005
Homo sapiens (Q7Z2E3)
brenda
Kijas, A.W.; Harris, J.L.; Harris, J.M.; Lavin, M.F.
Aprataxin forms a discrete branch in the HIT (histidine triad) superfamily of proteins with both DNA/RNA binding and nucleotide hydrolase activities
J. Biol. Chem.
281
13939-13948
2006
Homo sapiens (Q7Z2E3)
brenda
Moreira, M.C.; Barbot, C.; Tachi, N.; Kozuka, N.; Uchida, E.; Gibson, T.; Mendonca, P.; Costa, M.; Barros, J.; Yanagisawa, T.; Watanabe, M.; Ikeda, Y.; Aoki, M.; Nagata, T.; Coutinho, P.; Sequeiros, J.; Koenig, M.
The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin
Nat. Genet.
29
189-193
2001
Homo sapiens (Q7Z2E3)
brenda
Tumbale, P.; Appel, C.D.; Kraehenbuehl, R.; Robertson, P.D.; Williams, J.S.; Krahn, J.; Ahel, I.; Williams, R.S.
Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease
Nat. Struct. Mol. Biol.
18
1189-1195
2011
Schizosaccharomyces pombe (O74859), Schizosaccharomyces pombe, Schizosaccharomyces pombe ATCC 24843 (O74859)
brenda
Gong, Y.; Zhu, D.; Ding, J.; Dou, C.N.; Ren, X.; Gu, L.; Jiang, T.; Wang, D.C.
Crystal structures of aprataxin ortholog Hnt3 reveal the mechanism for reversal of 5-adenylated DNA
Nat. Struct. Mol. Biol.
18
1297-1299
2011
Schizosaccharomyces pombe (O74859), Schizosaccharomyces pombe, Schizosaccharomyces pombe ATCC 24843 (O74859)
brenda
Ahel, I.; Rass, U.; El-Khamisy, S.F.; Katyal, S.; Clements, P.M.; McKinnon, P.J.; Caldecott, K.W.; West, S.C.
The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates
Nature
443
713-716
2006
Gallus gallus (P61798), Gallus gallus, Mus musculus (Q7TQC5), Mus musculus
brenda
Tumbale, P.; Williams, J.S.; Schellenberg, M.J.; Kunkel, T.A.; Williams, R.S.
Aprataxin resolves adenylated RNA-DNA junctions to maintain genome integrity
Nature
506
111-115
2014
Saccharomyces cerevisiae (Q08702), Saccharomyces cerevisiae, Homo sapiens (Q7Z2E3), Homo sapiens, Saccharomyces cerevisiae ATCC 204508 (Q08702)
brenda
Becherel, O.J.; Jakob, B.; Cherry, A.L.; Gueven, N.; Fusser, M.; Kijas, A.W.; Peng, C.; Katyal, S.; McKinnon, P.J.; Chen, J.; Epe, B.; Smerdon, S.J.; Taucher-Scholz, G.; Lavin, M.F.
CK2 phosphorylation-dependent interaction between aprataxin and MDC1 in the DNA damage response
Nucleic Acids Res.
38
1489-1503
2010
Homo sapiens (Q7Z2E3)
brenda
Chauleau, M.; Jacewicz, A.; Shuman, S.
DNA3pp5G de-capping activity of aprataxin: effect of cap nucleoside analogs and structural basis for guanosine recognition
Nucleic Acids Res.
43
6075-6083
2015
Schizosaccharomyces pombe (O74859), Schizosaccharomyces pombe ATCC 24843 (O74859)
brenda
Hanaoka, K.; Tanaka, W.; Kayanuma, M.; Shoji, M.
A QM/MM study of the 5'-AMP DNA hydrolysis of aprataxin
Chem. Phys. Lett.
631-632
16-20
2015
Homo sapiens (Q7Z2E3)
-
brenda
Horton, J.K.; Stefanick, D.F.; Caglayan, M.; Zhao, M.L.; Janoshazi, A.K.; Prasad, R.; Gassman, N.R.; Wilson, S.H.
XRCC1 phosphorylation affects aprataxin recruitment and DNA deadenylation activity
DNA Repair
64
26-33
2018
Saccharomyces cerevisiae (Q08702), Homo sapiens (Q7Z2E3)
brenda
Tumbale, P.; Schellenberg, M.; Mueller, G.; Fairweather, E.; Watson, M.; Little, J.; Krahn, J.; Waddell, I.; London, R.; Williams, R.
Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease
EMBO J.
37
e98875
2018
Homo sapiens (Q7Z2E3), Homo sapiens
brenda
Garcia-Diaz, B.; Barca, E.; Balreira, A.; Lopez, L.C.; Tadesse, S.; Krishna, S.; Naini, A.; Mariotti, C.; Castellotti, B.; Quinzii, C.M.
Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway
Hum. Mol. Genet.
24
4516-4529
2015
Homo sapiens (Q7Z2E3), Homo sapiens
brenda
Schellenberg, M.J.; Tumbale, P.P.; Williams, R.S.
Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease
Prog. Biophys. Mol. Biol.
117
157-165
2015
Homo sapiens (Q7Z2E3)
brenda
Raponi, M.; Lancet, J.E.; Fan, H.; Dossey, L.; Lee, G.; Gojo, I.; Feldman, E.J.; Gotlib, J.; Morris, L.E.; Greenberg, P.L.; Wright, J.J.; Harousseau, J.L.; Loewenberg, B.; Stone, R.M.; De Porre, P.; Wang, Y.; Karp, J.E.
A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia
Blood
111
2589-2596
2008
Homo sapiens (Q7Z2E3)
brenda
Marriott, A.S.; Copeland, N.A.; Cunningham, R.; Wilkinson, M.C.; McLennan, A.G.; Jones, N.J.
Diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) is synthesized in response to DNA damage and inhibits the initiation of DNA replication
DNA Repair
33
90-100
2015
Cricetulus griseus (G3I8V7), Homo sapiens (Q7Z2E3)
brenda
Rass, U.; Ahel, I.; West, S.C.
Actions of aprataxin in multiple DNA repair pathways
J. Biol. Chem.
282
9469-9474
2007
Homo sapiens (Q7Z2E3)
brenda
Rass, U.; Ahel, I.; West, S.C.
Molecular mechanism of DNA deadenylation by the neurological disease protein aprataxin
J. Biol. Chem.
283
33994-34001
2008
Homo sapiens (Q7Z2E3), Homo sapiens
brenda
Tumbale, P.; Jurkiw, T.; Schellenberg, M.; Riccio, A.; O'Brien, P.; Williams, R.
Two-tiered enforcement of high-fidelity DNA ligation
Nat. Commun.
10
5431
2019
Homo sapiens
brenda
Gong, Y.; Zhu, D.; Ding, J.; Dou, C.N.; Ren, X.; Gu, L.; Jiang, T.; Wang, D.C.
Crystal structures of aprataxin ortholog Hnt3 reveal the mechanism for reversal of 5-adenylated DNA
Nat. Struct. Mol. Biol.
18
1297-1299
2011
Schizosaccharomyces pombe (O74859), Schizosaccharomyces pombe, Schizosaccharomyces pombe 972 (O74859)
brenda
Guranowski, A.; Wojdyla, A.; Zimny, J.; Wypijewska, A.; Kowalska, J.; Lukaszewicz, M.; Jemielity, J.; Darzynkiewicz, E.; Jagiello, A.; Bieganowski, P.
Recognition of different nucleotidyl-derivatives as substrates of reactions catalyzed by various HIT-proteins
New J. Chem.
34
888-893
2010
Arabidopsis thaliana (A0A2H1ZE58)
-
brenda
Sykora, P.; Croteau, D.L.; Bohr, V.A.; Wilson, D.M.
Aprataxin localizes to mitochondria and preserves mitochondrial function
Proc. Natl. Acad. Sci. USA
108
7437-7442
2011
Homo sapiens (Q7Z2E3), Homo sapiens
brenda