Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells

Kim, Chuna; Sung, Sang-Hyun; Kim, Jong Seo; Lee, Hyunji; Jung, Youngsuk; Shin, Sanghee; Kim, Eunkyeong; Seo, Jenny J.; Kim, Jun; Kim, Daeun; Niida, Hiroyuki; Kim, V. Narry; Park, Daechan; Lee, Jun-Ho

doi:10.1038/s41467-021-21341-x

Cited by 9 publications

(4 citation statements)

References 70 publications

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“…However, it is not known whether these ALT-like telomeres use the same process of maintenance as the ALT + cancer cells. Along this line, a recent work that revealed the existence of an ALT-like mechanism in Terc knock-out (KO) mouse stem cells, with a unique non-telomeric sequence (mTALT) [ 33 ]. This process might be related to the one used in wombat.…”

Section: Telomeres: Basic Molecular Mechanisms In An Evolutionary Contextmentioning

confidence: 99%

The Power of Stress: The Telo-Hormesis Hypothesis

Burbano

Gilson

2021

Cells

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Adaptative response to stress is a strategy conserved across evolution to promote survival. In this context, the groundbreaking findings of Miroslav Radman on the adaptative value of changing mutation rates opened new avenues in our understanding of stress response. Inspired by this work, we explore here the putative beneficial effects of changing the ends of eukaryotic chromosomes, the telomeres, in response to stress. We first summarize basic principles in telomere biology and then describe how various types of stress can alter telomere structure and functions. Finally, we discuss the hypothesis of stress-induced telomere signaling with hormetic effects.

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Section: Telomeres: Basic Molecular Mechanisms In An Evolutionary Contextmentioning

confidence: 99%

The Power of Stress: The Telo-Hormesis Hypothesis

Burbano

Gilson

2021

Cells

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“…Previous in vitro work using E14 mouse embryonic stem cells without mTR show that these cells grow for many population doublings before entering telomere crisis and inducing the alternative lengthening of telomeres pathway 36 . While these cells have been shown to extend their telomeres using a template known as mTALT, they do not demonstrate production of c-circles or formation of ALT-associated PML bodies which are characteristic of human ALT positive cancer cells 37 .…”

Section: Discussionmentioning

confidence: 94%

Loss of function ofAtrxleads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma

Pierpoint,

Floyd,

Wisdom

et al. 2023

Preprint

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The development of a telomere maintenance mechanism is essential for immortalization in human cancer. While most cancers elongate their telomeres by expression of telomerase, 10-15% of human cancers use a pathway known as alternative lengthening of telomeres (ALT). In this work, we developed a genetically engineered primary mouse model of sarcoma in CAST/EiJ mice which displays multiple molecular features of ALT activation after CRISPR/Cas9 introduction of oncogenicKrasG12Dand loss of function mutations ofTrp53andAtrx.In this model, we demonstrate that the loss ofAtrxcontributes to the development of ALT in an autochthonous tumor, and this process occurs independently of telomerase function by variation of mTR alleles. Furthermore, we find that telomere shortening from the loss of telomerase leads to higher chromosomal instability while loss ofAtrxand activation of ALT lead to an increase in telomeric instability, telomere sister chromatid exchange, c-circle production, and formation of ALT-associated promyelocytic leukemia bodies (APBs). The development of this primary mouse model of ALT could enable future investigations into therapeutic vulnerabilities of ALT activation and its mechanism of action.

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“…We focused our analysis on subtelomeric regions and the DNA damage-repair signatures generated during telomere evolution, especially telomere and subtelomere reconstruction by alternative lengthening of telomeres (ALT) mechanisms (Heaphy et al 2011;Sobinoff and Pickett 2017). ALT, which refers to alternative mechanisms that substitute telomerase function for telomere maintenance at the chromosome ends (Bryan et al 1995), is crucial in telomerase mutant eukaryotic cells such as those in yeast, Caenorhabditis elegans, mouse, and human, and can thus be used to model and interpret the evolution of TRM changes (Lundblad and Blackburn 1993;Bryan et al 1995;Seo et al 2015;Kim et al 2020;Kim et al 2021a;Kim et al 2021b). In these ALT models, homology-directed repair (HDR) mechanisms can add new telomeric components.…”

Section: Introductionmentioning

confidence: 99%

Telomeric repeat evolution in the phylum Nematoda revealed by high-quality genome assemblies and subtelomere structures

Lim,

Kim,

Kim

et al. 2023

Genome Res.

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Telomeres are composed of tandem arrays of telomeric-repeat motifs (TRMs) and telomere-binding proteins (TBPs), which are responsible for ensuring end-protection and end-replication of chromosomes. TRMs are highly conserved due to the sequence specificity of TBPs, although significant alterations in TRM have been observed in several taxa, except Nematoda. We used public whole-genome sequencing datasets to analyze putative TRMs of 100 nematode species and determined that three distinct branches included specific novel TRMs, suggesting that evolutionary alterations in TRMs occurred in Nematoda. We focused on one of the three branches, the Panagrolaimidae family, and performed a de novo assembly of four high-quality draft genomes of the canonical (TTAGGC) and novel TRM (TTAGAC) isolates; the latter genomes revealed densely clustered arrays of the novel TRM. We then comprehensively analyzed the subtelomeric regions of the genomes to infer how the novel TRM evolved. We identified DNA damage-repair signatures in subtelomeric sequences that were representative of consequences of telomere maintenance mechanisms by alternative lengthening of telomeres. We propose a hypothetical scenario in which TTAGAC-containing units are clustered in subtelomeric regions and pre-existing TBPs capable of binding both canonical and novel TRMs aided the evolution of the novel TRM in the Panagrolaimidae family.

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Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells

Cited by 9 publications

References 70 publications

The Power of Stress: The Telo-Hormesis Hypothesis

The Power of Stress: The Telo-Hormesis Hypothesis

Loss of function ofAtrxleads to activation of alternative lengthening of telomeres in a primary mouse model of sarcoma

Telomeric repeat evolution in the phylum Nematoda revealed by high-quality genome assemblies and subtelomere structures

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