Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 11 2023
04 11 2023
Historique:
received:
24
03
2022
accepted:
23
10
2023
medline:
6
11
2023
pubmed:
5
11
2023
entrez:
5
11
2023
Statut:
epublish
Résumé
Alternative lengthening of telomeres (ALT) is a telomere maintenance mechanism activated in ~10-15% of cancers, characterized by telomeric damage. Telomeric damage-induced long non-coding RNAs (dilncRNAs) are transcribed at dysfunctional telomeres and contribute to telomeric DNA damage response (DDR) activation and repair. Here we observed that telomeric dilncRNAs are preferentially elevated in ALT cells. Inhibition of C-rich (teloC) dilncRNAs with antisense oligonucleotides leads to DNA replication stress responses, increased genomic instability, and apoptosis induction selectively in ALT cells. Cell death is dependent on DNA replication and is increased by DNA replication stress. Mechanistically, teloC dilncRNA inhibition reduces RAD51 and 53BP1 recruitment to telomeres, boosts the engagement of BIR machinery, and increases C-circles and telomeric sister chromatid exchanges, without increasing telomeric non-S phase synthesis. These results indicate that teloC dilncRNA is necessary for a coordinated recruitment of DDR factors to ALT telomeres and it is essential for ALT cancer cells survival.
Identifiants
pubmed: 37925537
doi: 10.1038/s41467-023-42831-0
pii: 10.1038/s41467-023-42831-0
pmc: PMC10625592
doi:
Substances chimiques
RNA
63231-63-0
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7086Subventions
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Informations de copyright
© 2023. The Author(s).
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