Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity

Michele Menotta; Sara Biagiotti; Marzia Bianchi; Luciana Chessa; Mauro Magnani

doi:10.1074/jbc.M112.344473

Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity

J Biol Chem. 2012 Nov 30;287(49):41352-63. doi: 10.1074/jbc.M112.344473. Epub 2012 Oct 10.

Authors

Michele Menotta¹, Sara Biagiotti, Marzia Bianchi, Luciana Chessa, Mauro Magnani

Affiliation

¹ Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy. michele.menotta@uniurb.it

Abstract

Ataxia telangiectasia (AT) is a rare genetic disease, still incurable, resulting from biallelic mutations in the ataxia telangiectasia-mutated (ATM) gene. Recently, short term treatment with glucocorticoid analogues improved neurological symptoms characteristic of this syndrome. Nevertheless, the molecular mechanism involved in glucocorticoid action in AT patients is not yet known. Here we describe, for the first time in mammalian cells, a short direct repeat-mediated noncanonical splicing event induced by dexamethasone, which leads to the skipping of mutations upstream of nucleotide residue 8450 of ATM coding sequence. The resulting transcript provides an alternative ORF translated in a new ATM variant with the complete kinase domain. This miniATM variant was also highlighted in lymphoblastoid cell lines from AT patients and was shown to be likely active. In conclusion, dexamethasone treatment may partly restore ATM activity in ataxia telangiectasia cells by a new molecular mechanism that overcomes most of the mutations so far described within this gene.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Alternative Splicing
Ataxia Telangiectasia / metabolism*
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins / metabolism*
Cell Line
Codon
Cycloheximide / pharmacology
DNA-Binding Proteins / metabolism*
Dexamethasone / pharmacology*
Fungal Proteins
Genetic Variation
Genotype
Glucocorticoids / metabolism
HeLa Cells
Humans
Lymphocytes / metabolism
Models, Genetic
Mutation
Open Reading Frames
Phosphotransferases / metabolism
Protein Serine-Threonine Kinases / metabolism*
Protein Structure, Tertiary
Protein Synthesis Inhibitors / pharmacology
Single-Strand Specific DNA and RNA Endonucleases
Tumor Suppressor Proteins / metabolism*

Substances

Cell Cycle Proteins
Codon
DNA-Binding Proteins
Fungal Proteins
Glucocorticoids
Protein Synthesis Inhibitors
Tumor Suppressor Proteins
Dexamethasone
Cycloheximide
Phosphotransferases
ATM protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Endonuclease S1, Aspergillus
Single-Strand Specific DNA and RNA Endonucleases