RPA and POT1

Flynn, Rachel Litman; Chang, Sandy; Zou, Lee

doi:10.4161/cc.11.4.19061

Cited by 28 publications

(17 citation statements)

References 51 publications

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“…Mechanistically, the binding of POT1 to telomere ssDNA inhibits the localization of replication protein A (RPA), a ssDNA-damage sensor, at telomeres. As such, the loss of POT1 protein results in the illicit accumulation of RPA at the telomere, which persistently activates ATR signaling and activation of DNA-damage checkpoints to ultimately result in cellcycle arrest, senescence, or apoptosis (Flynn et al, 2012; O’Sullivan and Karlseder, 2010). …”

Section: Resultsmentioning

confidence: 99%

“…Specifically, the number of RPA foci that colocalize at telomeres in response to 5-FdU treatment increases in a manner that is dependent on telomerase activity. The concentration of cellular RPA is estimated to be nearly 3 million-fold higher than that of POT1 and TPP1 proteins (Flynn et al, 2012). Despite this extreme difference in cellular protein concentrations, POT1-TPP1 outcompetes RPA for binding of DNA exclusively with telomere sequence (Baumann and Price, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Zeng

Hernandez-Sanchez

et al. 2018

Cell Reports

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SUMMARY Telomerase, the end-replication enzyme, is reactivated in malignant cancers to drive cellular immortality. While this distinction makes telomerase an attractive target for anti-cancer therapies, most approaches for inhibiting its activity have been clinically ineffective. As opposed to inhibiting telomerase, we use its activity to selectively promote cytotoxicity in cancer cells. We show that several nucleotide analogs, including 5-fluoro-2′-deoxyuridine (5-FdU) triphosphate, are effectively incorporated by telomerase into a telomere DNA product. Administration of 5-FdU results in an increased number of telomere-induced foci, impedes binding of telomere proteins, activates the ATR-related DNA-damage response, and promotes cell death in a telomerase-dependent manner. Collectively, our data indicate that telomerase activity can be exploited as a putative anti-cancer strategy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Zeng

Hernandez-Sanchez

et al. 2018

Cell Reports

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“…3 These similar binding affinities suggest that CST should be considered in developing models of how these various ssDNA-binding proteins work together to regulate telomeres. 59 …”

Section: Discussionmentioning

confidence: 99%

Human CST Prefers G-Rich but Not Necessarily Telomeric Sequences

Hom

Wuttke

2017

Biochemistry

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The human CST (CTC1–STN1–TEN1) heterotrimeric complex plays roles in both telomere maintenance and DNA replication through its ability to interact with single-stranded DNA (ssDNA) of a variety of sequences. The precise sequence specificity required to execute these functions is unknown. Telomere-binding proteins have been shown to specifically recognize key telomeric sequence motifs within ssDNA while accommodating nonspecifically recognized sequences through conformationally plastic interfaces. To better understand the role CST plays in these processes, we have produced a highly purified heterotrimer and elucidated the sequence requirements for CST recognition of ssDNA in vitro. CST discriminates against random sequence and binds a minimal ssDNA comprised of three repeats of telomeric sequence. Replacement of individual nucleotides with their complement reveals that guanines are specifically recognized in a largely additive fashion and that specificity is distributed uniformly throughout the ligand. Unexpectedly, adenosines are also well tolerated at these sites, but cytosines are disfavored. Furthermore, sequences unrelated to the telomere repeat, yet still G-rich, bind CST well. Thus, CST is not inherently telomere-specific, but rather is a G-rich sequence binder. This biochemical activity is reminiscent of the yeast t-RPA and Tetrahymena thermophila CST complexes and is consistent with roles at G-rich sites throughout the genome.

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“…Flynn et al subsequently confirmed that TERRA can inhibit the ability of hnRNPA1 to displace RPA 67 . Due to the characteristic fluctuations in TERRA during cell cycle 49 , the group proposed a model in which tethering of TERRA to hnRNPA1 contributes to the RPA-to-POT1 switch on telomeric ssDNA 68 . In early to mid S phase, high levels of TERRA bind to hnRNPA1, which enables RPA to bind single-stranded telomeric DNA and release POT1 to enable telomere extension.…”

Section: Terra Regulates Telomere Length While Protecting Chromosome mentioning

confidence: 99%

Role of TERRA in the Regulation of Telomere Length

2015

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Telomere dysfunction is closely associated with human diseases such as cancer and ageing. Inappropriate changes in telomere length and/or structure result in telomere dysfunction. Telomeres have been considered to be transcriptionally silent, but it was recently demonstrated that mammalian telomeres are transcribed into telomeric repeat-containing RNA (TERRA). TERRA, a long non-coding RNA, participates in the regulation of telomere length, telomerase activity and heterochromatinization. The correct regulation of telomere length may be crucial to telomeric homeostasis and functions. Here, we summarize recent advances in our understanding of the crucial role of TERRA in the maintenance of telomere length, with focus on the variety of mechanisms by which TERRA is involved in the regulation of telomere length. This review aims to enable further understanding of how TERRA-targeted drugs can target telomere-related diseases.

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RPA and POT1

Cited by 28 publications

References 51 publications

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Administration of a Nucleoside Analog Promotes Cancer Cell Death in a Telomerase-Dependent Manner

Human CST Prefers G-Rich but Not Necessarily Telomeric Sequences

Role of TERRA in the Regulation of Telomere Length

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