Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

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Abstract

To escape replicative senescence, cancer cells have to overcome telomere attrition during DNA replication. Most of cancers rely on telomerase to extend and maintain telomeres, but 4–11% of cancers use a homologous recombination-based pathway called alternative lengthening of telomeres (ALT). ALT is prevalent in cancers from the mesenchymal origin and usually associates with poor clinical outcome. Given its critical role in protecting telomeres and genomic integrity in tumor cells, ALT is an Achilles heel of tumors and an attractive target for cancer therapy. Here, we review the recent progress in the mechanistic studies of ALT, and discuss the emerging therapeutic strategies to target ALT-positive cancers.

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Most cited references 70

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Alternative lengthening of telomeres: models, mechanisms and implications.

Anthony J Cesare, Roger R. Reddel (2010)

Unlimited cellular proliferation depends on counteracting the telomere attrition that accompanies DNA replication. In human cancers this usually occurs through upregulation of telomerase activity, but in 10-15% of cancers - including some with particularly poor outcome - it is achieved through a mechanism known as alternative lengthening of telomeres (ALT). ALT, which is dependent on homologous recombination, is therefore an important target for cancer therapy. Although dissection of the mechanism or mechanisms of ALT has been challenging, recent advances have led to the identification of several genes that are required for ALT and the elucidation of the biological significance of some phenotypic markers of ALT. This has enabled development of a rapid assay of ALT activity levels and the construction of molecular models of ALT.

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Systematic analysis of telomere length and somatic alterations in 31 cancer types

Floris Barthel, Wei Wei, Ming Tang … (2017)

Siyuan Zheng, Roel Verhaak and colleagues report an analysis of telomere lengths and somatic alterations in telomere-related pathways across 31 cancer types. Their study provides an overview of the molecular mechanisms driving TERT expression and activation of the ALT pathway, and identifies a subset of tumors with neither detectable TERT expression nor somatic alterations in ATRX or DAXX.

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Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.

Tracy Bryan, Anna Englezou, Luciano Dalla‐Pozza … (1997)

The gradual loss of DNA from the ends of telomeres has been implicated in the control of cellular proliferative potential. Telomerase is an enzyme that restores telomeric DNA sequences, and expression of its activity was thought to be essential for the immortalization of human cells, both in vitro and in tumor progression in vivo. Telomerase activity has been detected in 50-100% of tumors of different types, but not in most normal adult somatic tissues. It has also been detected in about 70% of human cell lines immortalized in vitro and in all tumor-derived cell lines examined to date. It has previously been shown that in vitro immortalized telomerase-negative cell lines acquire very long and heterogeneous telomeres in association with immortalization presumably via one or more novel telomere-lengthening mechanisms that we refer to as ALT (alternative lengthening of telomeres). Here we report evidence for the presence of ALT in a subset of tumor-derived cell lines and tumors. The maintenance of telomeres by a mechanism other than telomerase, even in a minority of cancers, has major implications for therapeutic uses of telomerase inhibitors.

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Author and article information

Contributors

Lee Zou: zou.lee@mgh.harvard.edu

Journal

Journal ID (nlm-ta): Cell Biosci

Journal ID (iso-abbrev): Cell Biosci

Title: Cell & Bioscience

Publisher: BioMed Central (London )

ISSN (Electronic): 2045-3701

Publication date (Electronic): 10 March 2020

Publication date PMC-release: 10 March 2020

Publication date Collection: 2020

Volume: 10

Electronic Location Identifier: 30

Affiliations

[1 ]Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129 USA

[2 ]GRID grid.32224.35, ISNI 0000 0004 0386 9924, Department of Pathology, , Massachusetts General Hospital, Harvard Medical School, ; Boston, MA 02114 USA

Article

Publisher ID: 391

DOI: 10.1186/s13578-020-00391-6

PMC ID: 7063710

PubMed ID: 32175073

SO-VID: 7b64b9b3-1000-4167-8333-7dfdd864905d

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 8 December 2019

Date accepted : 23 February 2020

Funding

Funded by: Massachusetts General Hospital

Award ID: MGH Cancer Center Excellence Award

Award ID: James and Patricia Endowed Chair

Award Recipient : Jia-Min Zhang Lee Zou

Custom metadata

ScienceOpen disciplines: Cell biology

Keywords: telomere,telomere maintenance mechanism,alternative lengthening of telomeres (alt),apbs,phase separation,alt telomeric dna synthesis,rad52,blm,fancm,clinical therapy

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ScienceOpen disciplines: Cell biology

Keywords: telomere, telomere maintenance mechanism, alternative lengthening of telomeres (alt), apbs, phase separation, alt telomeric dna synthesis, rad52, blm, fancm, clinical therapy

Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

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Most cited references 70

Alternative lengthening of telomeres: models, mechanisms and implications.

Systematic analysis of telomere length and somatic alterations in 31 cancer types

Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor-derived cell lines.

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