New human ATM variants are able to regain ATM functions in ataxia telangiectasia disease.
ATM/ATR crosstalk
Cell cycle checkpoint
Foci number
Oxidative stress
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
23 Nov 2022
23 Nov 2022
Historique:
received:
03
08
2022
accepted:
08
11
2022
revised:
28
10
2022
entrez:
24
11
2022
pubmed:
25
11
2022
medline:
29
11
2022
Statut:
epublish
Résumé
Ataxia telangiectasia is a rare neurodegenerative disease caused by biallelic mutations in the ataxia telangiectasia mutated gene. No cure is currently available for these patients but positive effects on neurologic features in AT patients have been achieved by dexamethasone administration through autologous erythrocytes (EryDex) in phase II and phase III clinical trials, leading us to explore the molecular mechanisms behind the drug action. During these investigations, new ATM variants, which originated from alternative splicing of ATM messenger, were discovered, and detected in vivo in the blood of AT patients treated with EryDex. Some of the new ATM variants, alongside an in silico designed one, were characterized and examined in AT fibroblast cell lines. ATM variants were capable of rescuing ATM activity in AT cells, particularly in the nuclear role of DNA DSBs recognition and repair, and in the cytoplasmic role of modulating autophagy, antioxidant capacity and mitochondria functionality, all of the features that are compromised in AT but essential for neuron survival. These outcomes are triggered by the kinase and further functional domains of the tested ATM variants, that are useful for restoring cellular functionality. The in silico designed ATM variant eliciting most of the functionality recover may be exploited in gene therapy or gene delivery for the treatment of AT patients.
Identifiants
pubmed: 36422718
doi: 10.1007/s00018-022-04625-3
pii: 10.1007/s00018-022-04625-3
pmc: PMC9691487
doi:
Substances chimiques
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
ATM protein, human
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
601Subventions
Organisme : H2020 European Research Council
ID : 667946
Informations de copyright
© 2022. The Author(s).
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