Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof

Claude, Eloïse; Decottignies, Anabelle

doi:10.1016/j.gde.2020.01.002

Cited by 31 publications

(35 citation statements)

References 58 publications

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“…Two distinct pathways have been discovered so far that ensure telomere maintenance in indefinitely dividing cancer cells: either telomerase reactivation or activation of an ALTernative mechanism of telomere maintenance. An accumulating body of evidence suggests that these two pathways are mutually exclusive and cannot co-exist in the same cell, at least under the physiological conditions of telomerase expression (Claude & Decottignies, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells circumvent entry into senescence and attain immortality by maintaining their telomere length via one of two, mutually exclusive, TMMs: (i) reactivation of the hTERT gene encoding the catalytic subunit of telomerase (TEL + cells) or (ii) hijacking a subset of cellular DNA replication and repair factors to perform "alternative lengthening of telomeres" (ALT + cells) (Shay & Wright, 2005;Cesare & Reddel, 2010). While 80-85% of cancer cells rely on telomerase activity, an estimated 10% of cancers use the ALT mechanism and its frequency may reach up to 20% in pediatric cancers (Shay & Bacchetti, 1997;Heaphy et al, 2011;Claude & Decottignies, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Alternatively, hTR may be deleterious to ALT + cells through its ability to activate the DNA-PK-dependent phosphorylation of hnRNPA1 (Ting et al, 2005;Ting et al, 2009;Le et al, 2013), a process known to promote the removal of RPA protein from telomeres (Flynn et al, 2011;Sui et al, 2015). Canonical functions of hTR, on the other hand, represent an added insult to ALT + cells as telomerase activity and ALT likely repress each other at telomeres (Claude & Decottignies, 2020).…”

Section: Introductionmentioning

confidence: 99%

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NHP2 downregulation counteracts h TR ‐mediated activation of the DNA damage response at ALT telomeres

et al. 2021

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About 10% of cancer cells employ the "alternative lengthening of telomeres" (ALT) pathway instead of reactivating the hTERT subunit of human telomerase. The hTR RNA subunit is also abnormally silenced in some ALT + cells not expressing hTERT, suggesting a possible negative non-canonical impact of hTR on ALT. Indeed, we show that ectopically expressed hTR reduces phosphorylation of ssDNA-binding protein RPA (p-RPA S33) at ALT telomeres by promoting the hnRNPA1-and DNA-PK-dependent depletion of RPA. The resulting defective ATR checkpoint signaling at telomeres impairs recruitment of the homologous recombination protein, RAD51. This induces ALT telomere fragility, increases POLD3-dependent C-circle production, and promotes the recruitment of the DNA damage marker 53BP1. In ALT + cells that naturally retain hTR expression, NHP2 H/ACA ribonucleoprotein levels are downregulated, likely in order to restrain DNA damage response (DDR) activation at telomeres through reduced 53BP1 recruitment. This unexpected role of NHP2 is independent from hTR's non-canonical function in modulating telomeric p-RPA S33. Collectively, our study shines new light on the interference between telomerase-and ALT-dependent pathways and unravels a crucial role for hTR and NHP2 in DDR regulation at ALT telomeres.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NHP2 downregulation counteracts h TR ‐mediated activation of the DNA damage response at ALT telomeres

et al. 2021

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“…Nevertheless, our finding that genome-wide 5hmC and R-loops overlap more robustly at the transcription termination site of active genes supports a model whereby TET enzymes act upstream of R-loop formation during transcription termination 34 . Telomeres, the nucleoprotein complexes found at the ends of linear eukaryotic chromosomes, can be maintained in proliferating ES and cancer cells by either the activity of telomerase or the alternative lengthening of telomeres (ALT) pathway 35 . ALT telomeres are maintained by mechanisms relying on homologous recombination (HR) between telomeric repeats.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops

et al. 2021

Preprint

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DNA oxidation by ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming. The conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) initiates developmental and cell-type-specific transcriptional programs through mechanisms that include changes in the chromatin structure. Here, we show that the presence of 5hmC in the transcribed DNA promotes the annealing of the nascent RNA to its template DNA strand, leading to the formation of an R-loop. The genome-wide distribution of 5hmC and R-loops show a positive correlation in mouse and human embryonic stem cells and overlap in half of all active genes. Moreover, R-loop resolution leads to differential expression of a subset of genes that are involved in crucial events during stem cell proliferation. Altogether, our data reveal that epigenetic reprogramming via TET activity promotes co-transcriptional R-loop formation, and disclose novel links between R-loops and the regulation of gene expression programs in stem cells.

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“…Certain tumour types seem to utilize ALT more frequently. Especially, in tumours originating from mesenchymal tissues, such as sarcomas, the ALT phenotype is overrepresented 7‐9 . Sarcomas are a heterogeneous cancer group and ALT status has been demonstrated as negative prognostic factor in some sarcoma subtypes 22‐25 .…”

Section: Introductionmentioning

confidence: 99%

Prevalence and potentially prognostic value of C‐circles associated with alternative lengthening of telomeres in canine appendicular osteosarcoma

Bicanová

Kreilmeier-Berger

Reifinger

et al. 2020

Vet Comparative Oncology

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Alternative lengthening of telomeres (ALT) is a telomerase‐independent telomere maintenance mechanism (TMM) with high prevalence in human osteosarcomas but remains unknown in canine osteosarcomas. The aim of this study was to evaluate the prevalence of ALT by detection of extra‐chromosomal circles of telomeric DNA and to assess clinical outcome in canine patients with spontaneous occurring appendicular osteosarcoma. Fifty dogs with histopathological confirmed osteosarcomas were included into this study. Medical records were retrospectively analysed for patient characteristics, oncologic therapy and survival. DNA was isolated from archived FFPE tumour tissue specimens and applied for C‐ and G‐circle assay (CCA and GCA) and for telomeric content (TC) measurement with radiolabeled probes. ALT activity was detected for 10 of 50 (20%) cases by CCA. Four CCA positive cases were detected even with input DNA below 1 ng and demonstrated the high sensitivity of CCA for canine tumours. G‐circles and TC were not suitable to distinguish CCA positive and negative cases. CCA‐status showed an association with male gender and Rottweiler breed. Dogs with CCA positive osteosarcomas had shorter overall survival times than patients with CCA‐tumours and CCA‐status was a significant prognostic factor besides treatment in the Cox proportional hazard model. These findings make canine osteosarcomas an interesting model for comparative TMM research, but future studies are warranted to investigate if CCA‐status can serve as novel prognostic marker.

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Telomere maintenance mechanisms in cancer: telomerase, ALT or lack thereof

Cited by 31 publications

References 58 publications

NHP2 downregulation counteracts h TR ‐mediated activation of the DNA damage response at ALT telomeres

NHP2 downregulation counteracts h TR ‐mediated activation of the DNA damage response at ALT telomeres

Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops

Prevalence and potentially prognostic value of C‐circles associated with alternative lengthening of telomeres in canine appendicular osteosarcoma

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