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ATRX modulates the escape from a telomere crisis

Geiller, Helen E.B., Harvey, Adam, Jones, Rhiannon E., Grimstead, Julia W., Cleal, Kez, Hendrickson, Eric A. and Baird, Duncan ORCID: https://orcid.org/0000-0001-8408-5467 2022. ATRX modulates the escape from a telomere crisis. Plos Genetics 18 (11) , e1010485. 10.1371/journal.pgen.1010485

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Abstract

Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immortality in human fibroblasts. Additionally, loss of ATRX combined with a telomere-driven crisis in HCT116 epithelial cancer cells led to the initiation of an ALT-like pathway. In these cells, a rapid and precise telomeric elongation and the induction of C-circles was observed; however, this process was transient and the telomeres ultimately continued to erode such that the cells either died or the escape from crisis was associated with telomerase activation. In both of these instances, telomere sequencing revealed that all alleles, irrespective of whether they were elongated, were enriched in variant repeat types, that appeared to be cell-line specific. Thus, our data show that the loss of ATRX combined with telomere dysfunction during crisis induces the ALT pathway in fibroblasts and enables a transient activation of ALT in epithelial cells.

Item Type: Article
Status: Published
Schools: Medicine
Publisher: Public Library of Science
Date of First Compliant Deposit: 4 November 2022
Date of Acceptance: 28 October 2022
Last Modified: 22 Nov 2022 13:25
URI: https://orca.cardiff.ac.uk/id/eprint/153989

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