TOP3A amplification and ATRX inactivation are mutually exclusive events in pediatric osteosarcomas using ALT.
ATRX
TOP3A
alternative lengthening of telomeres
osteosarcomas
telomeres
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
10 10 2022
10 10 2022
Historique:
revised:
13
07
2022
received:
09
02
2022
accepted:
14
07
2022
pubmed:
4
8
2022
medline:
12
10
2022
entrez:
3
8
2022
Statut:
ppublish
Résumé
In some types of cancer, telomere length is maintained by the alternative lengthening of telomeres (ALT) mechanism. In many ALT cancers, the α-thalassemia/mental retardation syndrome X-linked (ATRX) gene is mutated leading to the conclusion that the ATRX complex represses ALT. Here, we report that most high-grade pediatric osteosarcomas maintain their telomeres by ALT, and that the majority of these ALT tumors are ATRX wild-type (wt) and instead carry an amplified 17p11.2 chromosomal region containing TOP3A. We found that TOP3A was overexpressed in the ALT-positive ATRX-wt tumors consistent with its amplification. We demonstrated the functional significance of these results by showing that TOP3A overexpression in ALT cancer cells countered ATRX-mediated ALT inhibition and that TOP3A knockdown disrupted the ALT phenotype in ATRX-wt cells. Moreover, we report that TOP3A is required for proper BLM localization and promotes ALT DNA synthesis in ALT cell lines. Collectively, our results identify TOP3A as a major ALT player and potential therapeutic target.
Identifiants
pubmed: 35920001
doi: 10.15252/emmm.202215859
pmc: PMC9549729
doi:
Substances chimiques
Nuclear Proteins
0
DNA
9007-49-2
DNA Helicases
EC 3.6.4.-
ATRX protein, human
EC 3.6.4.12
X-linked Nuclear Protein
EC 3.6.4.12
TOP3A protein, human
EC 5.6.2.2
DNA Topoisomerases, Type I
EC 5.99.1.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e15859Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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