3.6.1.71	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	750307	
3.6.1.71	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	750417	
3.6.1.71	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	750390	
3.6.1.71	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	750720	
3.6.1.71	malfunction	mutation of aprataxin (APTX) is causing the heritable neurological disorder ataxia with oculomotor apraxia 1 (AOA1)	752086	
3.6.1.71	malfunction	mutations of the APTX gene cause neurological diseases such as ataxia oculomotor aparaxia type 1 (AOA1)	750307	
3.6.1.71	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	750390	
3.6.1.71	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	750307	
3.6.1.71	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	752086	
3.6.1.71	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	750307	
3.6.1.71	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	750390	
3.6.1.71	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	740679	
3.6.1.71	physiological function	aprataxin interacts with the repair proteins XRCC1, PARP-1 and p53 and colocalizes with XRCC1 along charged particle tracks on chromatin	740518	
3.6.1.71	physiological function	aprataxin is directly involved in DNA single-strand-break repair	740277	
3.6.1.71	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	741072	
3.6.1.71	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	754082	
3.6.1.71	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 492–574) of XRCC1. Poly(ADP–ribose) polymerase PARP-1 is also co-immunoprecipitated with APTX	739976	
3.6.1.71	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	754827	
3.6.1.71	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	750720	
3.6.1.71	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	740352	
3.6.1.71	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	755241	
3.6.1.71	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	741062	
3.6.1.71	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	752086	
3.6.1.71	physiological function	FD105 cells, lacking aprataxin, show a 5.7-fold increase in diadenosine 5', 5'''-P(1),P(4)-tetraphosphate (Ap4A) level	753396	
3.6.1.71	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	750390	
3.6.1.71	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	740519	
3.6.1.71	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	753396	
3.6.1.71	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	-, 741062	
3.6.1.71	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	703960	
3.6.1.71	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	750417	
3.6.1.71	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	754079	
3.6.1.71	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	739862	
3.6.1.71	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	741055