Break-induced replication promotes fragile telomere formation

Yang, Zhe; Takai, Kaori; Lovejoy, Courtney A.; Lange, Titia de

doi:10.1101/gad.328575.119

Cited by 53 publications

(65 citation statements)

References 55 publications

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“…When barriers prevent the completion of replication, cells can activate the mitotic DNA synthesis (MiDAS) pathway to resume synthesis before cell division. Following induction of telomeric 8oxoG, we observe a robust increase in single chromatid MiDAS events, which is consistent with other models of telomere replication stress (Min et al, 2017;Özer et al, 2018;Yang et al, 2020). We verified the telomere DDR response we observed was due to DNA replication by comparing replicating cells with serum-starved quiescent cells.…”

Section: Discussionsupporting

confidence: 90%

Telomeric 8-Oxoguanine Drives Rapid Premature Senescence In The Absence Of Telomere Shortening

et al. 2021

Preprint

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SUMMARYOxidative stress is a primary cause of cellular senescence and contributes to the pathogenesis of numerous human diseases. Oxidative damage to telomeric DNA is proposed to trigger premature senescence by accelerating telomere shortening. Here we tested this model directly using a precision tool to produce the common base lesion 8-oxo-guanine (8oxoG) exclusively at telomeres in human fibroblast and epithelial cells. A single induction of telomeric 8oxoG is sufficient to trigger multiple hallmarks of p53-dependent senescence. Telomeric 8oxoG activates ATM and ATR signaling, and enriches for markers of telomere dysfunction in replicating, but not quiescent cells. Acute 8oxoG production fails to shorten telomeres, but rather generates fragile sites and delayed mitotic DNA synthesis at telomeres, indicative of impaired replication. Based on our results we propose that oxidative stress promotes rapid senescence by producing oxidative base lesions which drive replication-dependent telomere fragility and dysfunction in the absence of shortening and shelterin loss.

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Section: Discussionsupporting

confidence: 90%

Telomeric 8-Oxoguanine Drives Rapid Premature Senescence In The Absence Of Telomere Shortening

et al. 2021

Preprint

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“…Precise molecular mechanisms leading to this latter phenotype still are only partially understood. However, recently it has been shown that DSB formation and the BIR (Break-Induced Replication) repair pathway were involved in formation of fragile telomeres ( Yang et al, 2020 ). Telomeric sister chromatid exchange could be detected by CO-FISH (Chromosome Orientation-FISH), a strand-specific variant of FISH and this phenotype is associated with telomeric replication defects ( Cherdyntseva and Gagos, 2020 ).…”

Section: Telomeric Dna Replication By the Conventional Replication Mamentioning

confidence: 99%

Telomere Replication: Solving Multiple End Replication Problems

Bonnell

Pasquier

Wellinger

2021

Front. Cell Dev. Biol.

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Eukaryotic genomes are highly complex and divided into linear chromosomes that require end protection from unwarranted fusions, recombination, and degradation in order to maintain genomic stability. This is accomplished through the conserved specialized nucleoprotein structure of telomeres. Due to the repetitive nature of telomeric DNA, and the unusual terminal structure, namely a protruding single stranded 3′ DNA end, completing telomeric DNA replication in a timely and efficient manner is a challenge. For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase. Despite the importance of telomerase in providing a mechanism for complete replication of telomeric ends, the majority of telomere replication is in fact carried out by the conventional DNA replication machinery. There is significant evidence demonstrating that progression of replication forks is hampered at chromosomal ends due to telomeric sequences prone to form secondary structures, tightly DNA-bound proteins, and the heterochromatic nature of telomeres. The telomeric loop (t-loop) formed by invasion of the 3′-end into telomeric duplex sequences may also impede the passage of replication fork. Replication fork stalling can lead to fork collapse and DNA breaks, a major cause of genomic instability triggered notably by unwanted repair events. Moreover, at chromosomal ends, unreplicated DNA distal to a stalled fork cannot be rescued by a fork coming from the opposite direction. This highlights the importance of the multiple mechanisms involved in overcoming fork progression obstacles at telomeres. Consequently, numerous factors participate in efficient telomeric DNA duplication by preventing replication fork stalling or promoting the restart of a stalled replication fork at telomeres. In this review, we will discuss difficulties associated with the passage of the replication fork through telomeres in both fission and budding yeasts as well as mammals, highlighting conserved mechanisms implicated in maintaining telomere integrity during replication, thus preserving a stable genome.

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“…As a whole, even if TRF1 in effect protects telomeres against damage, it is more dedicated to replicating the internal telomeric tract than actually capping the telomere terminus. TRF1 and BLM, which has been shown to resolve G4 structures [93], it has been proposed that TRF1 would recognize forks blocked by the formation of these conformations on the lagging strand [13,68] and recruit BLM, although what exactly TRF1 recognizes is still unknown. The situation seems clearer for TRF2.…”

Section: The Distinct Biological Roles Of Trf1 and Trf2mentioning

confidence: 99%

Multifunctionality of the Telomere-Capping Shelterin Complex Explained by Variations in Its Protein Composition

Ghilain

Gilson

Giraud-Panis

2021

Cells

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Protecting telomere from the DNA damage response is essential to avoid the entry into cellular senescence and organismal aging. The progressive telomere DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. In several organisms, including mammals, telomeres are protected by a protein complex named Shelterin that counteract at various levels the DNA damage response at chromosome ends through the specific function of each of its subunits. The changes in Shelterin structure and function during development and aging is thus an intense area of research. Here, we review our knowledge on the existence of several Shelterin subcomplexes and the functional independence between them. This leads us to discuss the possibility that the multifunctionality of the Shelterin complex is determined by the formation of different subcomplexes whose composition may change during aging.

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Break-induced replication promotes fragile telomere formation

Cited by 53 publications

References 55 publications

Telomeric 8-Oxoguanine Drives Rapid Premature Senescence In The Absence Of Telomere Shortening

Telomeric 8-Oxoguanine Drives Rapid Premature Senescence In The Absence Of Telomere Shortening

Telomere Replication: Solving Multiple End Replication Problems

Multifunctionality of the Telomere-Capping Shelterin Complex Explained by Variations in Its Protein Composition

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