A novel nonsense mutation in the APTX gene associated with delayed DNA single-strand break removal fails to enhance sensitivity to different genotoxic agents

Claudia Crimella, Orazio Cantoni, Andrea Guidarelli, Chiara Vantaggiato, Andrea Martinuzzi, Mara Fiorani, Catia Azzolini, Genny Orso, Nereo Bresolin, Maria Teresa Bassi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalHuman Mutation
Volume32
Issue number4
DOIs
Publication statusPublished - Apr 2011

Keywords

  • AOA1
  • APTX
  • DNA-SSB Repair
  • Hydrogen Peroxide
  • Methyl methane sulphonate

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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