Dexamethasone partially rescues ataxia telangiectasia-mutated (ATM) deficiency in ataxia telangiectasia by promoting a shortened protein variant retaining kinase activity.
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.
Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy. michele.menotta@uniurb.it
Michele
M
Menotta
Sara
S
Biagiotti
Marzia
M
Bianchi
Luciana
L
Chessa
Mauro
M
Magnani
D000483:Alleles; D017398:Alternative Splicing; D001260:Ataxia Telangiectasia / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D003062:Codon; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D005656:Fungal Proteins; D014644:Genetic Variation; D005838:Genotype; D005938:Glucocorticoids / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D016366:Open Reading Frames; D010770:Phosphotransferases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015719:Single-Strand Specific DNA and RNA Endonucleases; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D003062:Codon; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D005938:Glucocorticoids; D011500:Protein Synthesis Inhibitors; D025521:Tumor Suppressor Proteins; D003907:Dexamethasone; D003513:Cycloheximide; D010770:Phosphotransferases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C526098:Endonuclease S1, Aspergillus; D015719:Single-Strand Specific DNA and RNA Endonucleases