Affinage

APTX

Aprataxin · UniProt Q7Z2E3

Length
356 aa
Mass
40.7 kDa
Annotated
2026-06-09
60 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Aprataxin (APTX) is a DNA-end processing enzyme that resolves blocking lesions at DNA termini to enable strand break repair and safeguard genome integrity in both the nucleus and mitochondria (PMID:26256098, PMID:29934293). Mechanistically, APTX fuses a histidine triad (HIT) nucleotide hydrolase domain to a DNA minor-groove-binding C2H2 zinc finger; structural work on the orthologous and human enzymes defined a wedge-pivot-cut mechanism in which a helical wedge interrogates the base stack at nicks and ends while a pivot motif distorts terminal base-pairing to direct a 5'-adenylate (5'-AMP) adduct into the active site for hydrolytic removal, with a DNA-induced fit assembling the catalytically competent center (PMID:21984210, PMID:29934293). Beyond 5'-AMP resolution, recombinant APTX removes 3'-phosphoglycolate and 3'-phosphate blocking groups from DNA 3'-termini and cooperates with DNA polymerase beta and DNA ligase III to complete single-strand break repair (PMID:17519253). APTX is recruited to damage sites through XRCC1 (PMID:14755728, PMID:36940705) and also functions in double-strand break repair via a pathway distinct from XRCC4, since loss of APTX retards DSB repair and acts additively with XRCC4 depletion (PMID:36940705). APTX deficiency causes persistent unrepaired strand breaks, with mitochondrial DNA disproportionately affected and consequent mitochondrial dysfunction (PMID:26256098, PMID:21412945). Disease-associated mutations abolish APTX expression or catalysis and impair neural differentiation with accumulating single-strand breaks, linking APTX loss-of-function to the neurodegenerative disorder AOA1 (PMID:29934293, PMID:21412945, PMID:41136416).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2004 Medium

    Establishing how aprataxin connects to DNA repair machinery: the long-form isoform localizes to the nucleus and physically binds the scaffold protein XRCC1, placing aprataxin within a single-strand break repair complex.

    Evidence Yeast two-hybrid, reciprocal co-immunoprecipitation, and NLS deletion analysis

    PMID:14755728

    Open questions at the time
    • No in vitro reconstitution of repair activity
    • Functional consequence of the XRCC1 interaction not yet tested
    • Short-form role undefined
  2. 2007 High

    Defining a concrete catalytic activity: recombinant aprataxin removes 3'-phosphoglycolate and 3'-phosphate blocking groups at DNA 3'-termini and cooperates with pol beta and ligase III, with disease mutants losing this activity.

    Evidence In vitro biochemical assay with recombinant protein and active-site mutant controls

    PMID:17519253

    Open questions at the time
    • Did not address 5'-adenylate processing
    • Structural basis of substrate specificity unknown
    • In-cell relevance not directly shown
  3. 2011 High

    Resolving the catalytic mechanism: the crystal structure of an ortholog with DNA, AMP and Zn2+ revealed the HIT-zinc finger architecture and a wedge-pivot-cut strategy for recognizing and excising 5'-adenylate adducts, and mapped AOA1 mutations onto folding, active site, and pivot defects.

    Evidence X-ray crystallography of S. pombe aprataxin with site-directed mutagenesis and biochemical assays

    PMID:21984210

    Open questions at the time
    • Ortholog structure rather than human enzyme
    • Catalytic loop dynamics not resolved
    • Mechanism of XRCC1-mediated recruitment not addressed
  4. 2011 Medium

    Confirming the physiological repair role in patients: a nonsense mutation that abolishes aprataxin slows single-strand break repair in AOA1 patient cells after oxidative and alkylation damage.

    Evidence Patient cell lines, comet assay repair kinetics, western blot, cytotoxicity assay

    PMID:21412945

    Open questions at the time
    • No cytotoxic hypersensitivity detected
    • Single patient genotype
    • Does not link repair defect to neurodegeneration
  5. 2015 High

    Establishing compartment-specific function: APTX operates in both nucleus and mitochondria, and its loss causes persistent 5'-AMP intermediates and dysfunction specifically in mitochondrial DNA.

    Evidence Subcellular fractionation and in vitro repair assays from isogenic APTX+/+ and APTX-/- cells and mouse tissues

    PMID:26256098

    Open questions at the time
    • Mechanism of mitochondrial targeting not defined
    • Why mtDNA repair is slower than nuclear unresolved
    • Link to AOA1 neuropathology indirect
  6. 2018 High

    Refining the human mechanism and disease spectrum: human APTX structures on nicked RNA-DNA substrates confirmed the wedge-pivot-cut/induced-fit model, and a panel of 17 AOA1 variants showed most act by destabilizing the protein while rare alleles alter chemistry or allosterically modulate the active site.

    Evidence X-ray crystallography, solution NMR, in vitro deadenylation assays, comprehensive disease-variant panel

    PMID:29934293

    Open questions at the time
    • In-cell behavior of variants not assayed
    • Recruitment and partner dynamics not structurally defined
    • Mitochondrial vs nuclear context not distinguished
  7. 2023 Medium

    Extending APTX to double-strand break repair and clarifying recruitment dependencies: APTX is recruited to damage via XRCC1 (not XRCC4) and contributes to DSB repair through a pathway distinct from and additive with XRCC4.

    Evidence CRISPR/Cas9 knockout U2OS cells, laser micro-irradiation imaging, siRNA depletion, gammaH2AX foci, GFP end-joining reporter

    PMID:36940705

    Open questions at the time
    • Molecular substrate processed during DSB repair not identified
    • Identity of the distinct DSB pathway unresolved
    • Single cell line
  8. 2025 Medium

    Connecting catalytic loss to neuronal vulnerability: active-site histidine mutations that abolish APTX impair iPSC differentiation into neural progenitors and neurons while strand breaks and PARP-1 cleavage accumulate.

    Evidence CRISPR/Cas9 knockin iPSCs, neural differentiation, comet assay, PAR staining, PARP-1 cleavage western blot

    PMID:41136416

    Open questions at the time
    • Causal chain from strand breaks to differentiation defect not established
    • Decreased APE1 expression mechanism unknown
    • Single lab/genotype model

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XRCC1-mediated recruitment, the distinct DSB-repair pathway, and mitochondrial targeting are mechanistically coordinated to selectively protect neurons remains open.
  • DSB substrate and pathway partners undefined
  • Mechanism of mitochondrial import unknown
  • Basis for neuron-specific phenotype unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 4 GO:0140097 catalytic activity, acting on DNA 3 GO:0003677 DNA binding 2
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-73894 DNA Repair 3
Partners
XRCC1

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Aprataxin (long-form) localizes predominantly to the nucleus; the first nuclear localization signal near the amino terminus of the long-form is essential for nuclear localization. The long-form (but not the short-form) interacts with XRCC1 via yeast two-hybrid and co-immunoprecipitation, suggesting aprataxin and XRCC1 form a multiprotein complex involved in single-strand DNA break repair. Yeast two-hybrid, co-immunoprecipitation, nuclear localization signal deletion analysis Annals of neurology Medium 14755728
2007 Recombinant human aprataxin specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-termini (but not 3'-alpha,beta-unsaturated aldehyde ends) in an in vitro assay, and can cooperate with DNA polymerase beta and DNA ligase III to repair single-strand breaks bearing these damaged 3'-ends. Disease-associated mutant forms of aprataxin lack this removal activity. In vitro biochemical assay with recombinant protein, active-site mutant analysis Nucleic acids research High 17519253
2011 X-ray crystal structure of Schizosaccharomyces pombe Aprataxin (ortholog) in complex with DNA, AMP, and Zn2+ reveals active site and DNA interaction clefts formed by fusing a histidine triad (HIT) nucleotide hydrolase with a DNA minor groove-binding C2H2 zinc finger. An aprataxin helical 'wedge' interrogates the base stack for sensing DNA ends or nicks. The HIT-Znf, the wedge, and an '[F/Y]PK' pivot motif cooperate to distort terminal DNA base-pairing and direct 5'-adenylate into the active site, defining a wedge-pivot-cut catalytic mechanism for 5'-adenylate adduct recognition and removal. Structural and mutational data link AOA1 mutations to disruption of protein folding, the active site pocket, and the pivot motif. X-ray crystallography, site-directed mutagenesis, biochemical assays Nature structural & molecular biology High 21984210
2015 APTX is found in both the nucleus and mitochondria of eukaryotic cells. Repair of 5'-AMP DNA damage is significantly slower in mitochondrial protein extracts compared with nuclear extracts from the same human cell lines and mouse tissues. APTX deficiency causes persistent 5'-AMP DNA repair intermediates specifically in mitochondria (not nuclear genome), rendering mitochondrial DNA susceptible to damage and leading to mitochondrial dysfunction. Subcellular fractionation, in vitro repair assay with nuclear and mitochondrial extracts from APTX+/+ and APTX-/- cells Scientific reports High 26256098
2018 X-ray structures of human APTX engaging nicked RNA-DNA substrates provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolution. APTX uses a DNA-induced fit mechanism regulating active site loop conformations and assembly of a catalytically competent active center. Comprehensive biochemical, X-ray, and NMR analyses of 17 AOA1 variants show: 16 mutations affect APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and one dominant AOA1 variant allosterically modulates APTX active site conformations. X-ray crystallography, solution NMR, in vitro biochemical deadenylation assays, disease mutant panel analysis The EMBO journal High 29934293
2023 APTX knockout (CRISPR/Cas9) U2OS cells exhibit increased sensitivity to ionizing radiation and camptothecin with retarded DNA double-strand break repair (increased retained γH2AX foci). Recruitment of GFP-APTX to laser-induced DNA damage sites requires XRCC1 (siRNA depletion attenuates accumulation) but not XRCC4. APTX and XRCC4 depletion show additive inhibitory effects on double-strand break repair and end-joining, establishing that APTX acts in double-strand break repair through a pathway distinct from XRCC4. CRISPR/Cas9 knockout, live-cell laser micro-irradiation imaging, siRNA depletion, γH2AX foci assay, GFP-reporter end-joining assay Journal of radiation research Medium 36940705
2011 A novel nonsense APTX mutation (p.Gln298X) abolishes aprataxin protein expression in patient cells. APTX-deficient (AOA1) patient cells show significantly slower repair of DNA single-strand breaks induced by H2O2 or MMS, confirming aprataxin's role in SSB repair, while hypersensitivity to cytotoxicity was not detected. Patient cell lines, DNA strand break repair kinetics assay (comet assay), western blot, cytotoxicity assay Human mutation Medium 21412945
2025 APTX mutations at the active site histidine (p.H201P and p.H201R, introduced by CRISPR/Cas9 into iPSCs) abolish aprataxin protein expression. APTX-mutant iPSCs show diminished capacity to differentiate into neural progenitor cells and mature neurons, accumulate DNA single-strand breaks (detected by comet assay and poly(ADP-ribose) staining), show increased cleaved PARP-1/total PARP-1 ratio in NPCs and early immature neurons, and exhibit decreased APE1 expression during neural differentiation. CRISPR/Cas9 iPSC engineering, neural differentiation assay, comet assay, PAR staining, western blot, PARP-1 cleavage assay Cell death discovery Medium 41136416

Source papers

Stage 0 corpus · 60 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Spatial distribution and abundances of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) in mangrove sediments. Applied microbiology and biotechnology 85 20953601
2014 Osteoarthritis: From Palliation to Prevention: AOA Critical Issues. The Journal of bone and joint surgery. American volume 79 25100783
2015 The impact of temperature on microbial diversity and AOA activity in the Tengchong Geothermal Field, China. Scientific reports 74 26608685
2010 Characterization and quantification of ammonia-oxidizing archaea (AOA) and bacteria (AOB) in a nitrogen-removing reactor using T-RFLP and qPCR. Applied microbiology and biotechnology 68 20405121
2004 Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein. Annals of neurology 62 14755728
2007 Aprataxin, causative gene product for EAOH/AOA1, repairs DNA single-strand breaks with damaged 3'-phosphate and 3'-phosphoglycolate ends. Nucleic acids research 50 17519253
2017 Expression of sperm PLCζ and clinical outcomes of ICSI-AOA in men affected by globozoospermia due to DPY19L2 deletion. Reproductive biomedicine online 48 29339016
2021 Biotransformation of lincomycin and fluoroquinolone antibiotics by the ammonia oxidizers AOA, AOB and comammox: A comparison of removal, pathways, and mechanisms. Water research 47 33730544
2017 Response of Aerobic Granular Sludge to the Long-Term Presence of CuO NPs in A/O/A SBRs: Nitrogen and Phosphorus Removal, Enzymatic Activity, and the Microbial Community. Environmental science & technology 43 28832135
2020 Survival strategies of ammonia-oxidizing archaea (AOA) in a full-scale WWTP treating mixed landfill leachate containing copper ions and operating at low-intensity of aeration. Water research 40 33444853
2011 Ataxia with oculomotor apraxia type1 (AOA1): novel and recurrent aprataxin mutations, coenzyme Q10 analyses, and clinical findings in Italian patients. Neurogenetics 38 21465257
2011 Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease. Nature structural & molecular biology 33 21984210
2013 Community structure and transcript responses of anammox bacteria, AOA, and AOB in mangrove sediment microcosms amended with ammonium and nitrite. Applied microbiology and biotechnology 31 23455621
2015 Slow mitochondrial repair of 5'-AMP renders mtDNA susceptible to damage in APTX deficient cells. Scientific reports 21 26256098
2017 A More Comprehensive Community of Ammonia-Oxidizing Archaea (AOA) Revealed by Genomic DNA and RNA Analyses of amoA Gene in Subtropical Acidic Forest Soils. Microbial ecology 18 28808742
2018 Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease. The EMBO journal 15 29934293
2013 The role of TDP1 and APTX in mitochondrial DNA repair. Biochimie 15 24161509
2008 Ataxia with oculomotor apraxia type 1 (AOA1): clinical and neuropsychological features in 2 new patients and differential diagnosis. Journal of child neurology 15 18403580
2020 Responses of AOA and AOB activity and DNA/cDNA community structure to allylthiourea exposure in the water level fluctuation zone soil. Environmental science and pollution research international 12 32072408
2021 AOA-2 Derivatives as Outer Membrane Protein A Inhibitors for Treatment of Gram-Negative Bacilli Infections. Frontiers in microbiology 10 33643267
2021 Nutrient-Limited Enrichments of Nitrifiers From Soil Yield Consortia of Nitrosocosmicus-Affiliated AOA and Nitrospira-Affiliated NOB. Frontiers in microbiology 10 34322099
2013 Since when or how often? Dissociating the roles of age of acquisition (AoA) and lexical frequency in early visual word processing. Brain and language 10 23314421
2025 Comammox and AOA responses to ammonia loading rate in oligotrophic environments. Water research 9 39892190
2022 Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA? Open medicine (Warsaw, Poland) 9 35071778
2013 Vertical distribution of ammonia-oxidizing archaea (AOA) in the hyporheic zone of a eutrophic river in North China. World journal of microbiology & biotechnology 9 24242890
2006 Aprataxin (APTX) gene mutations resembling multiple system atrophy. Parkinsonism & related disorders 9 17049295
2021 Whole-genome sequencing, genome mining, metabolic reconstruction and evolution of pentachlorophenol and other xenobiotic degradation pathways in Bacillus tropicus strain AOA-CPS1. Functional & integrative genomics 8 33547987
2020 Sucralose causes non-selective CD4 and CD8 lymphotoxicity via probable regulation of the MAPK8/APTX/EID1 genes: An in vitro/in silico study. Clinical and experimental pharmacology & physiology 8 32542867
2011 A novel nonsense mutation in the APTX gene associated with delayed DNA single-strand break removal fails to enhance sensitivity to different genotoxic agents. Human mutation 8 21412945
2020 Biotransformation of pentachlorophenol by an indigenous Bacillus cereus AOA-CPS1 isolated from wastewater effluent in Durban, South Africa. Biodegradation 7 33011889
2020 Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents. PloS one 6 32750061
2017 Unexpectedly mild phenotype in an ataxic family with a two-base deletion in the APTX gene. Journal of the neurological sciences 5 28566184
2012 A novel mutation in the aprataxin (APTX) gene in an Iranian individual suffering early-onset ataxia with oculomotor apraxia type 1(AOA1) disease. Iranian biomedical journal 5 23183622
2005 Early-onset ataxia with oculomotor apraxia with a novel APTX mutation. Pediatric neurology 5 15876520
1987 Interaction of AOA 39, D600, verapamil and diltiazem with cardiac cholinergic effects. Archives internationales de pharmacodynamie et de therapie 5 3592862
2020 Generation and characterization of induced pluripotent stem cell (iPSC) line (JUCTCi002-A) from a patient with ataxia with oculomotor apraxia type 1 (AOA1) harboring a homozygous mutation in the APTX gene. Stem cell research 4 32769066
2014 Niche differentiation of ammonia-oxidising archaea (AOA) and bacteria (AOB) in response to paper and pulp mill effluent. Microbial ecology 4 24563191
2025 Enrichment of Nitrosocosmicus-AOA in situ and their vertical distribution characteristics in aerated biofilters. Environmental research 3 40220886
2024 Draft genome sequence of Bacillus velezensis strains AOA1 and AKS2, the potential plant growth-promoting rhizobacteria. Microbiology resource announcements 3 38411072
2023 APTX acts in DNA double-strand break repair in a manner distinct from XRCC4. Journal of radiation research 3 36940705
2020 Role of tetrachloro-1,4-benzoquinone reductase in phenylalanine hydroxylation system and pentachlorophenol degradation in Bacillus cereus AOA-CPS1. International journal of biological macromolecules 3 32535205
2015 Complete APTX deletion in a patient with ataxia with oculomotor apraxia type 1. BMC medical genetics 3 26285866
2024 Both AOA and AOB contribute to nitrification and show linear correlation with nitrate leaching in purple soils with a wide nitrogen gradient. Environmental research 2 39577732
2021 Heterozygous deletion in exon 6 of STEX gene causing ataxia with oculomotor apraxia type 2 (AOA-2) with ovarian failure. BMJ case reports 2 34193451
2020 Cloning, overexpression, purification, characterization and structural modelling of a metabolically active Fe2+ dependent 2,6-dichloro-p-hydroquinone 1,2-dioxygenase (CpsA) from Bacillus cereus strain AOA-CPS_1. International journal of biological macromolecules 2 32512093
2017 Identification of a novel mutation in the APTX gene associated with ataxia-oculomotor apraxia. Cold Spring Harbor molecular case studies 2 28652255
2013 Progressive ataxia associated with ocular apraxia type 1 (AOA1) with a presence of a novel mutation on the aprataxin gene. Annals of Indian Academy of Neurology 2 23956581
2025 Enhanced synergistic interaction between AOA and anammox bacteria: a novel mechanism for stability under nitrite shock loading in PN-A systems. Bioresource technology 1 41453533
2024 The different responses of AOA and AOB communities to irrigation systems in the semi-arid region of Northeast China. Frontiers in microbiology 1 38774509
2022 Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings. Molecular neurobiology 1 35420381
2022 Case report: A novel APTX p.Ser168GlufsTer19 mutation in a Chinese family with ataxia with oculomotor apraxia type 1. Frontiers in neurology 1 36119692
2022 Ataxia with oculomotor apraxia type 1 associated with mutation in the APTX gene: A case study and literature review. Experimental and therapeutic medicine 1 36382100
2021 Classic Pentachlorophenol Hydroxylating Phenylalanine 4-Monooxygenase from Indigenous Bacillus tropicus Strain AOA-CPS1: Cloning, Overexpression, Purification, Characterization and Structural Homology Modelling. Applied biochemistry and biotechnology 1 34417677
2026 Two distinct patterns for advanced simultaneous nitrogen and phosphorus removal treating low C/N wastewater in a low DO anaerobic/oxic/anoxic-aerobic granular sludge (AOA-AGS) system. Environmental research 0 41856230
2026 Engineering the anammox pathway in a full-scale AOA process for industrial wastewater treatment. Water research 0 41880703
2026 Oxygen depletion shifts niche partitioning of AOA and AOB in Bohai Sea sediments. Marine pollution bulletin 0 42105660
2025 Evaluation of DNA Methylation and Expression of DLK1 and MEG3 Genes in Placenta and Umbilical Cord Blood Samples of Infertile People after ICSI-AOA Method. Reproductive sciences (Thousand Oaks, Calif.) 0 40011392
2025 Nitrosocosmicus AOA-driven anammox bacteria enrichment in counter-current aerated biofilters: Unraveling the start-up mechanism of the novel autotrophic nitrification-denitrification process. Bioresource technology 0 41086973
2025 Induced pluripotent stem cells carrying novel APTX mutations presented defective neural differentiation with the accumulation of DNA single-strand breaks. Cell death discovery 0 41136416
2024 Heterozygous APTX mutation associated with atypical multiple system atrophy-like phenotype: A case report. Parkinsonism & related disorders 0 38555792

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