Special Issue "ALT: From Telomere Maintenance Mechanisms to Proposed Therapies"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 November 2019).

Special Issue Editors

Prof. Antonella Sgura
Website SciProfiles
Guest Editor
Department of Science, University of Rome "Roma Tre", Rome, Italy
Interests: Telomere, oxidative stress, genotoxicity, epigenetic, ALT in human primary fibroblasts, senescence, DNA damage, ionizing radiations
Dr. Ion Udroiu

Guest Editor
Department of Science, University of Rome "Roma Tre", Rome, Italy
Interests: Genotoxicity, senescence, telomerase inhibitors, telomere biology, telomere evolution.
Dr. Francesco Berardinelli

Guest Editor
Department of Science, University of Rome "Roma Tre", Rome, Italy
Interests: Telomeric G-quadruplex, telomere and telomerase targeting, ALT, cancer, DNA damage, ionizing radiations.

Special Issue Information

Dear Colleagues,

Alternative Lengthening of Telomeres (ALT) is one of the Telomere Maintenance Mechanisms (TMM). Because the mechanism was unknown at the beginning, many studies were aimed to point out the molecular markers of ALT, since the only distinctive known feature at the time was telomere length maintenance in absence of telomerase. Nowadays, ALT cells have been characterized by different markers widely accepted, including chromatin modifications, but the mechanism and the events triggering ALT are still little known. Several experimental evidences came in favour of a recombinogenic mechanism, fuelling the need to clarify whether ALT is nothing but homologous recombination (HR) or it is a telomere-specific type of HR. The complexity of the ALT mechanisms is one of the keys to unfold the heterogeneous behavior of ALT tumors in terms of disease progression and response to treatment. As a consequence, while specific telomerase drugs have been discovered and are presently employed in clinical applications, the therapeutic relevance of molecular players involved in ALT is still debated. Furthermore, considering the role of telomere in chromosome structure and therefore in genome stability and in tumor progression, the mechanisms involved in telomere maintenance need to be clarified and great efforts are needed to allow an in-depth comprehension of the ALT molecular mechanisms; especially in order to develop specific and effective anticancer strategies.

Prof. Antonella Sgura
Dr. Ion Udroiu
Dr. Francesco Berardinelli
Guest Editors

Manuscript Submission Information

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Keywords

  • telomere biology
  • alternative lengthening of telomeres
  • telomerase
  • DNA damage
  • cancer
  • telomere maintenance mechanism
  • chromatin
  • genome stability
  • chromosome

Published Papers (5 papers)

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Research

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Open AccessArticle
G-quadruplex Stabilization Fuels the ALT Pathway in ALT-positive Osteosarcoma Cells
Genes 2020, 11(3), 304; https://doi.org/10.3390/genes11030304 - 13 Mar 2020
Cited by 4
Abstract
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue ALT: From Telomere Maintenance Mechanisms to Proposed Therapies)
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Open AccessArticle
BRCA2 Deletion Induces Alternative Lengthening of Telomeres in Telomerase Positive Colon Cancer Cells
Genes 2019, 10(9), 697; https://doi.org/10.3390/genes10090697 - 10 Sep 2019
Cited by 3
Abstract
BRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion [...] Read more.
BRCA1/2 are tumor suppressor genes controlling genomic stability also at telomeric and subtelomeric loci. Their mutation confers a predisposition to different human cancers but also sensitivity to antitumor drugs including poly(ADP-ribose) polymerase (PARP) inhibitors and G-quadruplex stabilizers. Here we demonstrate that BRCA2 deletion triggers TERRA hyperexpression and alternative lengthening mechanisms (ALT) in colon cancer cells in presence of telomerase activity. This finding opens the question if cancer patients bearing BRCA2 germline or sporadic mutation are suitable for anti-telomerase therapies, or how ALT activation could influence the short or long-term response to anti-PARP inhibitors or anti-G-quadruplex therapies. Full article
(This article belongs to the Special Issue ALT: From Telomere Maintenance Mechanisms to Proposed Therapies)
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Review

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Open AccessReview
ALT: A Multi-Faceted Phenomenon
Genes 2020, 11(2), 133; https://doi.org/10.3390/genes11020133 - 27 Jan 2020
Cited by 3
Abstract
One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) [...] Read more.
One of the hallmarks of cancer cells is their indefinite replicative potential, made possible by the activation of a telomere maintenance mechanism (TMM). The majority of cancers reactivate the reverse transcriptase, telomerase, to maintain their telomere length but a minority (10% to 15%) utilize an alternative lengthening of telomeres (ALT) pathway. Here, we review the phenotypes and molecular markers specific to ALT, and investigate the significance of telomere mutations and sequence variation in ALT cell lines. We also look at the recent advancements in understanding the different mechanisms behind ALT telomere elongation and finally, the progress made in identifying potential ALT-targeted therapies, including those already in use for the treatment of both hematological and solid tumors. Full article
(This article belongs to the Special Issue ALT: From Telomere Maintenance Mechanisms to Proposed Therapies)
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Open AccessReview
Alternative Lengthening of Telomeres and Chromatin Status
Genes 2020, 11(1), 45; https://doi.org/10.3390/genes11010045 - 30 Dec 2019
Cited by 1
Abstract
Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation [...] Read more.
Telomere length is maintained by either telomerase, a reverse transcriptase, or alternative lengthening of telomeres (ALT), a mechanism that utilizes homologous recombination (HR) proteins. Since access to DNA for HR enzymes is regulated by the chromatin status, it is expected that telomere elongation is linked to epigenetic modifications. The aim of this review is to elucidate the epigenetic features of ALT-positive cells. In order to do this, it is first necessary to understand the telomeric chromatin peculiarities. So far, the epigenetic nature of telomeres is still controversial: some authors describe them as heterochromatic, while for others, they are euchromatic. Similarly, ALT activity should be characterized by the loss (according to most researchers) or formation (as claimed by a minority) of heterochromatin in telomeres. Besides reviewing the main works in this field and the most recent findings, some hypotheses involving the role of telomere non-canonical sequences and the possible spatial heterogeneity of telomeres are given. Full article
(This article belongs to the Special Issue ALT: From Telomere Maintenance Mechanisms to Proposed Therapies)
Open AccessReview
Alternative Lengthening of Telomeres (ALT) in Tumors and Pluripotent Stem Cells
Genes 2019, 10(12), 1030; https://doi.org/10.3390/genes10121030 - 10 Dec 2019
Cited by 2
Abstract
A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) [...] Read more.
A telomere consists of repeated DNA sequences (TTAGGG)n as part of a nucleoprotein structure at the end of the linear chromosome, and their progressive shortening induces DNA damage response (DDR) that triggers cellular senescence. The telomere can be maintained by telomerase activity (TA) in the majority of cancer cells (particularly cancer stem cells) and pluripotent stem cells (PSCs), which exhibit unlimited self-proliferation. However, some cells, such as telomerase-deficient cancer cells, can add telomeric repeats by an alternative lengthening of the telomeres (ALT) pathway, showing telomere length heterogeneity. In this review, we focus on the mechanisms of the ALT pathway and potential clinical implications. We also discuss the characteristics of telomeres in PSCs, thereby shedding light on the therapeutic significance of telomere length regulation in age-related diseases and regenerative medicine. Full article
(This article belongs to the Special Issue ALT: From Telomere Maintenance Mechanisms to Proposed Therapies)
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