A novel nonsense mutation in the APTX gene associated with delayed DNA single‐strand break removal fails to enhance sensitivity to different genotoxic agents
| Autor: | Genny Orso, Chiara Vantaggiato, Nereo Bresolin, Mara Fiorani, Catia Azzolini, Claudia Crimella, Maria Teresa Bassi, Andrea Martinuzzi, Andrea Guidarelli, Orazio Cantoni |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Ataxia
Cerebellar Ataxia DNA Repair Apraxias Methyl methane sulphonate Nonsense mutation aptX Biology APTX medicine.disease_cause Ataxia Telangiectasia chemistry.chemical_compound Single-Stranded Genetics medicine Humans DNA Breaks Single-Stranded Oculomotor apraxia Codon Gene Genetics (clinical) Spinocerebellar Degenerations Aprataxin Mutation AOA1 DNA-SSB Repair Hydrogen Peroxide Base Sequence Codon Nonsense DNA DNA Damage DNA-Binding Proteins Hypoalbuminemia Methyl Methanesulfonate Mutagens Nuclear Proteins Oxidants Pedigree DNA Breaks medicine.disease Molecular biology Nonsense chemistry medicine.symptom |
| Zdroj: | Human Mutation. 32 |
| ISSN: | 1098-1004 1059-7794 |
| DOI: | 10.1002/humu.21464 |
| Popis: | APTX is the gene involved in ataxia with oculomotor apraxia type 1 (AOA1), a recessive disorder with early-onset cerebellar ataxia, oculomotor apraxia and peripheral neuropathy. The encoded protein, aprataxin, is a DNA repair protein processing the products of abortive ligations, 5′-adenylated DNA. We describe a novel nonsense mutation in APTX, c.892C>T (p.Gln298X), segregating in two AOA1 patients and leading to the loss of aprataxin protein in patient's cells. These cells, while exhibiting reduced catalase activity, are not hypersensitive to toxicity elicited by H2O2 exposure at either physiologic or ice-bath temperature. On the other hand, the rate of repair of DNA single-strand-breaks (SSBs) induced in both conditions is always significantly slower in AOA1 cells. By using the alkylating agent methyl methane sulphonate (MMS) we confirmed the association of the APTX mutation with a DNA repair defect in the absence of detectable changes in susceptibility to toxicity. These results, while consistent with a role of aprataxin in the repair of SSBs induced by H2O2, or MMS, demonstrate that other mechanisms may be recruited in AOA1 cells to complete the repair process, although at a slower rate. Lack of hypersensitivity to the oxidant, or MMS, also implies that delayed repair is not per se a lethal event. © 2011 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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