Premature transcription termination at the expanded GAA repeats and aberrant alternative polyadenylation contributes to the Frataxin transcriptional deficit in Friedreich's ataxia.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
10 10 2022
10 10 2022
Historique:
received:
14
04
2022
revised:
12
05
2022
accepted:
05
06
2022
pubmed:
17
6
2022
medline:
15
10
2022
entrez:
16
6
2022
Statut:
ppublish
Résumé
Frataxin deficiency in Friedreich's ataxia results from transcriptional downregulation of the FXN gene caused by expansion of the intronic trinucleotide guanine-adenine-adenine (GAA) repeats. We used multiple transcriptomic approaches to determine the molecular mechanism of transcription inhibition caused by long GAAs. We uncovered that transcription of FXN in patient cells is prematurely terminated upstream of the expanded repeats leading to the formation of a novel, truncated and stable RNA. This FXN early terminated transcript (FXN-ett) undergoes alternative, non-productive splicing and does not contribute to the synthesis of functional frataxin. The level the FXN-ett RNA directly correlates with the length of the longer of the two expanded GAA tracts. Targeting GAAs with antisense oligonucleotides or excision of the repeats eliminates the transcription impediment, diminishes expression of the aberrant FXN-ett, while increasing levels of FXN mRNA and frataxin. Non-productive transcription may represent a common phenomenon and attractive therapeutic target in diseases caused by repeat-mediated transcription aberrations.
Identifiants
pubmed: 35708503
pii: 6607932
doi: 10.1093/hmg/ddac134
pmc: PMC9558844
doi:
Substances chimiques
Arsenicals
0
Iron-Binding Proteins
0
Oligonucleotides, Antisense
0
RNA, Messenger
0
gallium arsenide
27FC46GA44
Guanine
5Z93L87A1R
Gallium
CH46OC8YV4
Adenine
JAC85A2161
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
3539-3557Subventions
Organisme : NINDS NIH HHS
ID : R01 NS081366
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS121038
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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