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ALT: A Multi-Faceted Phenomenon
Article

G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells

1
Department of Science, Roma Tre University, I-00146 Rome, Italy
2
BPM-CNR Institute of Molecular Biology and Pathology, National Research Council, 00185 Rome, Italy
3
Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2020, 11(3), 304; https://doi.org/10.3390/genes11030304
Received: 31 January 2020 / Revised: 20 February 2020 / Accepted: 9 March 2020 / Published: 13 March 2020
(This article belongs to the Special Issue ALT: From Telomere Maintenance Mechanisms to Proposed Therapies)
Most human tumors maintain telomere lengths by telomerase, whereas a portion of them (10–15%) uses a mechanism named alternative lengthening of telomeres (ALT). The telomeric G-quadruplex (G4) ligand RHPS4 is known for its potent antiproliferative effect, as shown in telomerase-positive cancer models. Moreover, RHPS4 is also able to reduce cell proliferation in ALT cells, although the influence of G4 stabilization on the ALT mechanism has so far been poorly investigated. Here we show that sensitivity to RHPS4 is comparable in ALT-positive (U2OS; SAOS-2) and telomerase-positive (HOS) osteosarcoma cell lines, unlinking the telomere maintenance mechanism and RHPS4 responsiveness. To investigate the impact of G4 stabilization on ALT, the cardinal ALT hallmarks were analyzed. A significant induction of telomeric doublets, telomeric clusterized DNA damage, ALT-associated Promyelocytic Leukaemia-bodies (APBs), telomere sister chromatid exchanges (T-SCE) and c-circles was found exclusively in RHPS4-treated ALT cells. We surmise that RHPS4 affects ALT mechanisms through the induction of replicative stress that in turn is converted in DNA damage at telomeres, fueling recombination. In conclusion, our work indicates that RHPS4-induced telomeric DNA damage promotes overactivation of telomeric recombination in ALT cells, opening new questions on the therapeutic employment of G4 ligands in the treatment of ALT positive tumors. View Full-Text
Keywords: telomeres; ALT; G-quadruplex; RHPS4; replicative stress telomeres; ALT; G-quadruplex; RHPS4; replicative stress
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MDPI and ACS Style

Amato, R.; Valenzuela, M.; Berardinelli, F.; Salvati, E.; Maresca, C.; Leone, S.; Antoccia, A.; Sgura, A. G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells. Genes 2020, 11, 304. https://doi.org/10.3390/genes11030304

AMA Style

Amato R, Valenzuela M, Berardinelli F, Salvati E, Maresca C, Leone S, Antoccia A, Sgura A. G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells. Genes. 2020; 11(3):304. https://doi.org/10.3390/genes11030304

Chicago/Turabian Style

Amato, Roberta, Martina Valenzuela, Francesco Berardinelli, Erica Salvati, Carmen Maresca, Stefano Leone, Antonio Antoccia, and Antonella Sgura. 2020. "G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells" Genes 11, no. 3: 304. https://doi.org/10.3390/genes11030304

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