The differential processing of telomeres in response to increased telomeric transcription and RNA–DNA hybrid accumulation

Balk, Bettina; Dees, Martina; Bender, Katharina; Luke, Brian

doi:10.4161/rna.27798

Cited by 42 publications

(42 citation statements)

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“…ICP8 has been shown to bind RNA and stabilize R-loops (Boehmer, 2004), consistent with our observation that it associates with telomeres actively transcribing TERRA. TERRA transcripts are known to form R-loops at telomeres suggesting that TERRA transcription may be sufficient to induce a high-affinity single stranded DNA substrate for ICP8 (Balk et al, 2014; Pfeiffer et al, 2013). ICP8 also associates with components of cellular DNA repair and recombination machinery (de Bruyn Kops and Knipe, 1994; Taylor et al, 2003), that are also known to associate with cellular telomeres (Dejardin and Kingston, 2009).…”

Section: Discussionmentioning

confidence: 99%

HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

et al. 2014

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Summary Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat-containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1, and loss of the telomere repeat DNA signal. The HSV-1 encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. shRNA depletion of TPP1 increases viral replication, arguing that TPP1inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins and ICP8 null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated pre-replication foci and promotes viral genomic replication.

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Section: Discussionmentioning

confidence: 99%

HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

et al. 2014

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“…Further, elevated levels of TERRA are characteristic of human ALT cell lines established from tumors or immortalized in vitro (LOVEJOY et al 2012;ARORA et al 2014). TERRA could stabilize Dloop structures to facilitate recombination between telomeres (BALK et al 2013;BALK et al 2014). Given the recent evidence suggesting that ncRNAs can drive the physical association between regions of the genome (ENGREITZ et al 2013), it is also possible that telomere-associated TERRA could tether a telomere in trans, promoting the proximity between individual telomeres necessary to support recombination.…”

Section: Discussionmentioning

confidence: 99%

“…G-rich TERRA can form RNA-DNA hybrids at the telomere, resulting in a triple-stranded structure called an "R-loop"; R-loops are antagonized by the activity of RNase H, which specifically degrades RNA engaged in such hybrids (BALK et al 2013;ARORA et al 2014;BALK et al 2014). Recent evidence indicates that telomeric R-loops may actively engage in HR in telomerase-negative human and yeast cells.…”

Section: Introductionmentioning

confidence: 99%

“…Recent evidence indicates that telomeric R-loops may actively engage in HR in telomerase-negative human and yeast cells. For example, depletion of RNase H1 (alone or in combination with RNase H2) results in accumulated RNA-DNA hybrids at telomeres and greater telomere recombination in cis, while RNase H overexpression leads to decreased telomere recombination in pre-senescent cells and compromised telomere maintenance in ALT cells (BALK et al 2013;ARORA et al 2014;BALK et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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RNA-DNA hybrids support recombination-based telomere maintenance in fission yeast

Bennett

Liu

et al. 2018

Preprint

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Running Title: Telomere maintenance by recombination Keywords: telomere / recombination / RNA-DNA hybrid / TERRA / shelterin / ALT pathway 2 ABSTRACT A subset of cancers rely on telomerase-independent mechanisms to maintain their chromosome ends. The predominant "alternative lengthening of telomeres" pathway appears dependent on homology-directed repair (HDR) to maintain telomeric DNA. However, the molecular changes needed for cells to productively engage in telomeric HDR are poorly understood. To gain new insights into this transition, we monitored the state of telomeres during serial culture of fission yeast (Schizosaccharomyces pombe) lacking the telomerase recruitment factor Ccq1. Rad52 is loaded onto critically short telomeres shortly after germination despite continued telomere erosion, suggesting that recruitment of recombination factors is not sufficient to maintain telomeres in the absence of telomerase function. Instead, survivor formation coincides with the derepression of telomeric repeat-containing RNA (TERRA). In this context, degradation of TERRA associated with the telomere in the form of R-loops drives a severe growth crisis, ultimately leading to a novel type of survivor with linear chromosomes and altered cytological telomere characteristics, including the loss of the shelterin component Rap1 (but not the TRF1/TRF2 orthologue, Taz1) from the telomere. We demonstrate that deletion of Rap1 is protective in this context, preventing the growth crisis that is otherwise triggered by degradation of telomeric R-loops in survivors with linear chromosomes. These findings suggest that up-regulation of telomere-engaged TERRA or altered recruitment of shelterin components can support telomerase-independent telomere maintenance.

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“…The exact molecular nature of the telomeres when survivors emerge is not clear. In budding yeast, the highly complex mixture found in a survivor culture hints at very heterogeneous telomeric states, defined by telomere length (Chang, Dittmar, & Rothstein, 2011;Grandin & Charbonneau, 2009;Lebel et al, 2009), recruitment of factors involved in telomere processing (Claussin & Chang, 2015), and the presence of RNA-DNA hybrids (Balk, Dees, Bender, & Luke, 2014;Misino, Bonetti, Luke-Glaser, & Luke, 2018;Yu, Kao, & Lin, 2014). The checkpoint status of the cell might also affect the generation of survivors (Tsai, Tseng, Chang, Lin, & Teng, 2002).…”

Section: Postsenescence Survivalmentioning

confidence: 99%

The many types of heterogeneity in replicative senescence

Teixeira

2019

Yeast

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Replicative senescence, which is induced by telomere shortening, underlies the loss of regeneration capacity of organs and is ultimately detrimental to the organism. At the same time, it is required to protect organisms from unlimited cell proliferation that may arise from numerous stimuli or deregulations. One important feature of replicative senescence is its high level of heterogeneity and asynchrony, which promote genome instability and senescence escape. Characterizing this heterogeneity and investigating its sources are thus critical to understanding the robustness of replicative senescence. Here we review the different aspects of senescence driven by telomere attrition that are subject to variation in Saccharomyces cerevisiae, the current understanding of the molecular processes at play, and the consequences of heterogeneity in replicative senescence.

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The differential processing of telomeres in response to increased telomeric transcription and RNA–DNA hybrid accumulation

Cited by 42 publications

References 41 publications

HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

HSV-1 Remodels Host Telomeres to Facilitate Viral Replication

RNA-DNA hybrids support recombination-based telomere maintenance in fission yeast

The many types of heterogeneity in replicative senescence

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