Hyperextended telomeres promote formation of C-circle DNA in telomerase positive human cells.

Autor:	Jones CY; Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA., Williams CL; Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA., Moreno SP; Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA., Morris DK; Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA., Mondello C; Institute of Molecular Genetics, Luigi Luca Cavalli-Sforza, National Research Council, Pavia, Italy., Karlseder J; Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, USA., Bertuch AA; Division of Hematology/Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA; Texas Children's Cancer Center, Texas Children's Hospital, Houston, Texas, USA. Electronic address: abertuch@bcm.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 May; Vol. 299 (5), pp. 104665. Date of Electronic Publication: 2023 Mar 30.
DOI:	10.1016/j.jbc.2023.104665
Abstrakt:	Telomere length maintenance is crucial to cancer cell immortality. Up to 15% of cancers utilize a telomerase-independent, recombination-based mechanism termed alternative lengthening of telomeres (ALT). Currently, the primary ALT biomarker is the C-circle, a type of circular DNA with extrachromosomal telomere repeats (cECTRs). How C-circles form is not well characterized. We investigated C-circle formation in the human cen3tel cell line, a long-telomere, telomerase+ (LTT+) cell line with progressively hyper-elongated telomeres (up to ∼100 kb). cECTR signal was observed in 2D gels and C-circle assays but not t-circle assays, which also detect circular DNA with extrachromosomal telomere repeats. Telomerase activity and C-circle signal were not separable in the analysis of clonal populations, consistent with C-circle production occurring within telomerase+ cells. We observed similar cECTR results in two other LTT+ cell lines, HeLa1.3 (∼23 kb telomeres) and HeLaE1 (∼50 kb telomeres). In LTT+ cells, telomerase activity did not directly impact C-circle signal; instead, C-circle signal correlated with telomere length. LTT+ cell lines were less sensitive to hydroxyurea than ALT+ cell lines, suggesting that ALT status is a stronger contributor to replication stress levels than telomere length. Additionally, the DNA repair-associated protein FANCM did not suppress C-circles in LTT+ cells as it does in ALT+ cells. Thus, C-circle formation may be driven by telomere length, independently of telomerase and replication stress, highlighting limitations of C-circles as a stand-alone ALT biomarker. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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