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Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies

Abstract

Cancer cells establish replicative immortality by activating a telomere-maintenance mechanism (TMM), be it telomerase or the alternative lengthening of telomeres (ALT) pathway. Targeting telomere maintenance represents an intriguing opportunity to treat the vast majority of all cancer types. Whilst telomerase inhibitors have historically been heralded as promising anticancer agents, the reality has been more challenging, and there are currently no therapeutic options for cancer types that use ALT despite their aggressive nature and poor prognosis. In this Review, we discuss the mechanistic differences between telomere maintenance by telomerase and ALT, the current methods used to detect each mechanism, the utility of these tests for clinical diagnosis, and recent developments in the therapeutic strategies being employed to target both telomerase and ALT. We present notable developments in repurposing established therapeutic agents and new avenues that are emerging to target cancer types according to which TMM they employ. These opportunities extend beyond inhibition of telomere maintenance, by finding and exploiting inherent weaknesses in the telomeres themselves to trigger rapid cellular effects that lead to cell death.

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Fig. 1: Telomerase-mediated telomere lengthening and the therapeutics that inhibit this process.
Fig. 2: Chromatin remodelling creates an ALT permissive state.
Fig. 3: Resolution of replication stress at telomeres using ALT.
Fig. 4: Multiple DNA repair pathways are engaged at telomeres using ALT.

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Acknowledgements

The authors acknowledge the Australian Medical Research Future Fund (2007488) for funding. The authors thank Alexander Sobinoff, Robert Lu and Robyn Yeh for proofreading the manuscript.

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J.G. researched data for the article. J.G. and H.A.P. contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Hilda A. Pickett.

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H.A.P. is a co-founder and shareholder of Tessellate Bio. J.G. declares no competing interests.

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Glossary

Homology-directed repair

(HDR). A type of double-strand break repair where a homologous section on a sister chromatid is used as a template to guide DNA synthesis and repair. It involves processing of the double-strand break by the MRN complex to create single-stranded overhangs, prior to RAD51-mediated or RAD52-mediated strand invasion of the sister chromatid to enable DNA extension. Intermediates are then resolved to complete the repair.

Rolling circle amplification reaction

An isothermal DNA or RNA amplification reaction where circular oligonucleotides (for example, C-circles) function as a template for the DNA or RNA polymerase.

5′ Resection

A process where the blunt end of a double-strand break undergoes nucleolytic degradation in the 5′ to 3′ direction to leave a 3′ single-stranded overhang.

Telomere replication

Replication of the telomere repeat tracks.

C-strand fill-in

Telomeres consist of G-strand (5′-TTAGGG-3′) and complementary C-strand (3′-AATCCC-5′) repeats. Telomerase extends the G-strand, resulting in a G-rich single-stranded 3′ overhang. C-strand fill-in is the process by which the complementary C-strand is synthesized by DNA polymerase α-primase 12 to convert the single-stranded DNA of the 3′ overhang into double-stranded DNA.

G-quadruplexes

(G4s). Non-canonical secondary structures formed by guanine (G)-rich DNA sequences.

Displacement-loops

(D-loops). D-loops form when single-stranded DNA invades a section of double-stranded DNA, causing it to separate into a loop structure.

Strand invasion

Single-stranded DNA invades a section of double-stranded DNA with sequence homology.

Osteoid

An unmineralized organic tissue that becomes calcified and contributes to the bone matrix.

Replisome

A protein complex that can exhibit helicase, primase and DNA polymerase activities to replicate DNA of both the leading and lagging strand. During ALT, the replisome consists of proliferating cell nuclear antigen (PCNA), replication factor C (RFC) and DNA polymerase δ (Polδ).

Branch migration

A process that occurs after strand invasion, where one strand of DNA is processively exchanged for another at Holliday junctions or D-loops, resulting in movement of the junction.

Homologous recombination

(HR). The most common form of HDR, whereby exchange of genetic material occurs between two homologous chromosomes.

ALT-associated promyelocytic leukaemia bodies

(APBs). Membraneless structures formed by phase separation that promote the aggregation of homologous recombination proteins, nucleases, telomere-associated proteins, PML proteins and telomeric DNA. APBs are a biomarker of alternative lengthening of telomeres (ALT).

Small ubiquitin-like modifier

(SUMO). Units that are covalently attached to proteins post-translationally in a process known as sumoylation. This can alter several properties of the protein, including protein stability, localization, and addition or removal of protein–protein binding sites.

Break-induced replication

Recombination-dependent DNA synthesis that initiates from a double-strand break and occurs following strand invasion mediated by RAD51 or RAD52.

Extrachromosomal telomeric repeats

(ECTRs). Linear and circular extrachromosomal copies of telomeric sequences that are generated during homologous recombination in cells using ALT, including C-circles and t-circles. ECTRs are a biomarker of ALT.

Myelofibrosis

A rare type of bone marrow cancer that prevents the production of blood cells, leading to anaemia and scar tissue in the bone marrow.

Transcription elongation

A step in RNA transcription that occurs following initiation and prior to termination when the RNA sequence is synthesized complementary to the DNA template.

Inhibitory concentration 50

(IC50). The dose of an agent required to inhibit 50% of cell growth.

Epitope spreading

The process by which epitopes, distinct from the inducing epitope of a vaccine, become major targets of the immune response.

Macrocyclic compound

A compound made up of chemical ring structures that each consist of 12 or more carbon atoms.

Porphyrin

A molecule that consists of a ring of four linked heterocyclic groups that can be held together by a central metal atom.

Non-homologous end-joining

A repair pathway where double-strand breaks are ligated together. Non-homologous end-joining (NHEJ) consists of either canonical NHEJ or alternative NHEJ. In the canonical pathway, the two ends of the DNA are bound by Ku70 and Ku80 and DNA-PKcs, which come together to form the synaptic complex. This is then ligated together by the ligase IV–XRCC4 complex. Alternative NHEJ occurs independently of canonical NHEJ proteins and involves the direct joining of short sequence homologies (microhomologies).

Mitotic DNA synthesis

The process of DNA repair synthesis during mitosis.

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Gao, J., Pickett, H.A. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. Nat Rev Cancer 22, 515–532 (2022). https://doi.org/10.1038/s41568-022-00490-1

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