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

Gao, Jixuan; Pickett, Hilda A.

doi:10.1038/s41568-022-00490-1

Cited by 124 publications

(87 citation statements)

References 294 publications

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“…Cancer cells must maintain their telomere length for their sustained proliferation, and they do so by either activating telomerase, a ribonucleoprotein complex, or by utilizing a HR-based recombination pathway, referred to as alternative lengthening of telomeres (ALT). Both telomerase and ALT are targets in cancer therapy [ 125 ]. CSB has been reported to promote both telomerase-dependent and ALT-mediated telomere maintenance [ 18 , 19 ], making CSB an attractive anti-cancer target.…”

Section: Csb and Telomeresmentioning

confidence: 99%

“…Replication stress at telomeres is elevated in ALT cancer cells compared to telomerase-expressing cancer cells [ 125 ]. Recent work from our lab has demonstrated that CSB promotes telomeric recruitment of a number of proteins engaged in homology-directed repair, including MRE11, NBS1, BRCA1, BLM, RPA, and POLD3 in ALT cells [ 18 ].…”

Section: Csb and Telomeresmentioning

confidence: 99%

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Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Walker

Zhu

2022

IJMS

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A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

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Section: Csb and Telomeresmentioning

confidence: 99%

Section: Csb and Telomeresmentioning

confidence: 99%

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Walker

Zhu

2022

IJMS

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“…Although the majority of ALT-positive tumors and cell lines are ATRX-deficient, the underlying genetics and mutational status of SMARCAL1 and ATRX should be considered in future pre-clinical and clinical studies that focus on ALT mechanisms and associated drug sensitivities. Finally, SMARCAL1-deficient ALT-positive models may be useful tools for transiently suppressing the ALT phenotype or phenotype-switching (ALT to telomerase) to create isogenic model systems comparing therapeutic vulnerabilities according to telomere maintenance mechanisms 9 .…”

Section: Discussionmentioning

confidence: 99%

“…The remaining cases maintain telomeres through ALT 2 . ALT utilizes homology directed repair (HDR) mechanisms to maintain telomere length and is characterized by frequent ATRX loss-of-function mutations, high levels of DNA replication stress, and a remodeling of telomeric chromatin to an epigenetic state that is permissive to homologous recombination [4][5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells

Liu

Diplas

et al. 2022

Preprint

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Telomere maintenance mechanisms are a hallmark of cancer and are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase for telomere maintenance, a subset of cancers (~10-15%) use telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT is characterized by elevated replication stress at telomeres, telomere synthesis via homology directed-repair mechanisms, and is frequently associated with mutations in the ATRX gene. Because ALT is absent in non-malignant proliferating cells, therapeutic strategies targeting ALT-mediated telomere synthesis is an area of significant translational and clinical interest. We previously showed that a subset of adult GBM patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene. SMARCAL1 is an annealing helicase involved in replication fork remodeling and the resolution of replication stress. In this study, we used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated telomere synthesis and gliomagenesis in vivo. Our results show that inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. Further, SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, suggesting that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis. In summary, we show that SMARCAL1 loss-of-function mutations are permissive to ALT and promote gliomagenesis. We also established isogenic model systems that permit the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the molecular mechanisms of ALT and for identifying novel anti-cancer therapeutics that target the ALT phenotype.

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“…ALT mechanisms that depend on homologous recombination can be observed also in human telomerase-negative immortalized cell lines and in 10–15% of human cancers, which use them to re-elongate their telomeres and gain unlimited proliferative potential [ 179 , 180 ]. A plasmid tag inserted into a single telomere in mouse or human ALT cells was found to be copied to other telomeres or duplicated in its original location without the involvement of other telomeres [ 181 , 182 , 183 ].…”

Section: Telomerase-independent Re-stabilization Of Telomere Lengthmentioning

confidence: 99%

To Fix or Not to Fix: Maintenance of Chromosome Ends Versus Repair of DNA Double-Strand Breaks

Casari

Gnugnoli

Rinaldi

et al. 2022

Cells

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Early work by Muller and McClintock discovered that the physical ends of linear chromosomes, named telomeres, possess an inherent ability to escape unwarranted fusions. Since then, extensive research has shown that this special feature relies on specialized proteins and structural properties that confer identity to the chromosome ends, thus allowing cells to distinguish them from intrachromosomal DNA double-strand breaks. Due to the inability of conventional DNA replication to fully replicate the chromosome ends and the downregulation of telomerase in most somatic human tissues, telomeres shorten as cells divide and lose this protective capacity. Telomere attrition causes the activation of the DNA damage checkpoint that leads to a cell-cycle arrest and the entering of cells into a nondividing state, called replicative senescence, that acts as a barrier against tumorigenesis. However, downregulation of the checkpoint overcomes this barrier and leads to further genomic instability that, if coupled with re-stabilization of telomeres, can drive tumorigenesis. This review focuses on the key experiments that have been performed in the model organism Saccharomyces cerevisiae to uncover the mechanisms that protect the chromosome ends from eliciting a DNA damage response, the conservation of these pathways in mammals, as well as the consequences of their loss in human cancer.

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

Cited by 124 publications

References 294 publications

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells

To Fix or Not to Fix: Maintenance of Chromosome Ends Versus Repair of DNA Double-Strand Breaks

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