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TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.

ABSTRACT: The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin caused by loss of ATRX/DAXX independently of H3.3 deposition. Moreover, our data indicate that TZAP binding to telomeres induces telomere dysfunction and ALT-like activity, resulting in the generation of t-circles and c-circles in a Bloom-Topoisomerase IIIα-RMI1-RMI2 (BTR)-dependent manner.

SUBMITTER: Moreno SP

PROVIDER: S-EPMC10066556 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.

Moreno Sara Priego SP Fusté Javier Miralles JM Kaiser Melanie M Li Julia Su Zhou JSZ Nassour Joe J Haggblom Candy C Denchi Eros Lazzerini EL Karlseder Jan J

iScience 20230314 4

The appropriate regulation of telomere length homeostasis is crucial for the maintenance of genome integrity. The telomere-binding protein TZAP has been suggested to regulate telomere length by promoting t-circle and c-circle excisions through telomere trimming, yet the molecular mechanisms by which TZAP functions at telomeres are not understood. Using a system based on TZAP overexpression, we show that efficient TZAP recruitment to telomeres occurs in the context of open telomeric chromatin cau ...[more]

PMID: 37013192

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Project description:Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.

Dataset Information

TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.

Publications

TZAP overexpression induces telomere dysfunction and ALT-like activity in ATRX/DAXX-deficient cells.

Similar Datasets

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