Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks - PubMed (original) (raw)

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Alternative lengthening of telomeres: from molecular mechanisms to therapeutic outlooks

Jia-Min Zhang et al. Cell Biosci. 2020.

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.

Keywords: ALT telomeric DNA synthesis; APBs; Alternative lengthening of telomeres (ALT); BLM; Clinical therapy; FANCM; Phase separation; RAD52; Telomere; Telomere maintenance mechanism.

© The Author(s) 2020.

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Conflict of interest statement

Competing interestsThe authors declares that they have no competing interests.

Figures

Fig. 1

Fig. 1

Framework of the ALT pathways. (Upper section) The replication stress at telomeres may be a trigger for ALT activation. The accumulation of R-loops, G-quadruplexes, and DNA single-strand breaks at telomeres may interfere with DNA replication, leading to collapse of replication forks and formation of one-ended DSBs. (Lower left section) the replication stress or DNA damage at telomeres may induce SUMOylation of telomere proteins, which recruit PML and trigger APB formation through SUMO/SIM-mediated LLPS. The clustering of telomeres and enrichment of DNA repair, recombination, and replication proteins in APBs may drive ALT efficiently. (Lower right section) In APBs, BIR is triggered by the one-ended DSBs at telomeres. ALT can take place through RAD52-dependent and -independent BIR pathways. The conservative DNA replication during BIR is dependent on POLD3/POLD4, promoted by BLM, and inhibited by SLX4. C-circles are generated by the RAD52-independent BIR pathway, which is suppressed by RAD51 and MRE11

Fig. 2

Fig. 2

Positive and negative regulators of ALT. (Left) Positive regulators of ALT discussed in this article. (Middle) Major events that occur during the process of ALT. (Right) Negative regulators of ALT discussed in this article

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