Xenopus laevis Ctc1-Stn1-Ten1 (xCST) Protein Complex Is Involved in Priming DNA Synthesis on Single-stranded DNA Template in Xenopus Egg Extract

Nakaoka, Hidenori; Nishiyama, Atsuya; Saito, Motoki; Ishikawa, Fuyuki

doi:10.1074/jbc.m111.263723

Cited by 61 publications

(67 citation statements)

References 37 publications

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“…Surprisingly, our results suggest that the telomeric association of polα is independent of Stn1 ( Figure 6). Together with recent report showing that polα recruitment to ss DNA is independent of xStn1 in Xenopus extract [49], we conclude that CST is likely dispensable for polα recruitment to telomeres and that unidentified proteins may recruit polα to telomeres.…”

Section: Discussionmentioning

confidence: 87%

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

2012

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Telomere maintenance is critical for genome stability. The newly-identified Ctc1/Stn1/Ten1 complex is important for telomere maintenance, though its precise role is unclear. We report here that depletion of hStn1 induces catastrophic telomere shortening, DNA damage response, and early senescence in human somatic cells. These phenotypes are likely due to the essential role of hStn1 in promoting efficient replication of lagging-strand telomeric DNA. Downregulation of hStn1 accumulates single-stranded G-rich DNA specifically at lagging-strand telomeres, increases telomere fragility, hinders telomere DNA synthesis, as well as delays and compromises telomeric C-strand synthesis. We further show that hStn1 deficiency leads to persistent and elevated association of DNA polymerase α (polα) to telomeres, suggesting that hStn1 may modulate the DNA synthesis activity of polα rather than controlling the loading of polα to telomeres. Additionally, our data suggest that hStn1 is unlikely to be part of the telomere capping complex. We propose that the hStn1 assists DNA polymerases to efficiently duplicate lagging-strand telomeres in order to achieve complete synthesis of telomeric DNA, therefore preventing rapid telomere loss.

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Section: Discussionmentioning

confidence: 87%

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

2012

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“…Null mutations in STN1 or TEN1 are not lethal, and cells do not accumulate single-stranded G-rich telomere DNA (Sun et al, 2009), implying that the essential contributions of CST components are not universally conserved. CST orthologs (CTC1/STN1/TEN1) have been reported in vertebrates and plants (Song et al, 2008;Miyake et al, 2009;Surovtseva et al, 2009;Nakaoka et al, 2012). Although CONSERVED TELOMERE MAINTENANCE COMPONENT1 (CTC1) shares no sequence similarity with Cdc13 from budding yeast, CST complexes appear to function in similar capacities across eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

“…As in yeast, vertebrate and plant CST interact with polymerase (pol) a (Casteel et al, 2009;Price et al, 2010;Huang et al, 2012;Nakaoka et al, 2012). Indeed, mammalian CTC1 and STN1 were first identified as pol a accessory factors (Casteel et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, mammalian CTC1 and STN1 were first identified as pol a accessory factors (Casteel et al, 2009). Biochemical studies reveal that vertebrate CST stimulates pol a/primase activity on telomeric substrates (Dai et al, 2010;Huang et al, 2012;Nakaoka et al, 2012) and promotes new origin firing at nontelomeric sites (Stewart et al, 2012). CST also interacts with the shelterin components TPP1 in human cells ) and POT1b in mice (Wu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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MERISTEM DISORGANIZATION1Encodes TEN1, an Essential Telomere Protein That Modulates Telomerase Processivity inArabidopsis

et al. 2013

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Telomeres protect chromosome ends from being recognized as DNA damage, and they facilitate the complete replication of linear chromosomes. CST [for CTC1(Cdc13)/STN1/TEN1] is a trimeric chromosome end binding complex implicated in both aspects of telomere function. Here, we characterize TEN1 in the flowering plant Arabidopsis thaliana. We report that TEN1 (for telomeric pathways in association with Stn1, which stands for suppressor of cdc thirteen) is encoded by a previously characterized gene, MERISTEM DISORGANIZATION1 (MDO1). A point mutation in MDO1, mdo1-1/ten1-3 (G77E), triggers stem cell differentiation and death as well as a constitutive DNA damage response. We provide biochemical and genetic evidence that ten1-3 is likely to be a null mutation. As with ctc1 and stn1 null mutants, telomere tracts in ten1-3 are shorter and more heterogeneous than the wild type. Mutants also exhibit frequent telomere fusions, increased single-strand telomeric DNA, and telomeric circles. However, unlike stn1 or ctc1 mutants, telomerase enzyme activity is elevated in ten1-3 mutants due to an increase in repeat addition processivity. In addition, TEN1 is detected at a significantly smaller fraction of telomeres than CTC1. These data indicate that TEN1 is critical for telomere stability and also plays an unexpected role in modulating telomerase enzyme activity.

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“…Furthermore, our data suggest that C:S also regulates C‐strand maintenance by DNA Pol‐α (Figure 7c). Both CTC1 and STN1 have been shown to interact with DNA Pol‐α, with a recent report suggesting that STN1 stimulates the switch between RNA priming and DNA synthesis activities of DNA Pol‐α (Ganduri & Lue, 2017; Huang, Dai & Chai, 2012; Nakaoka, Nishiyama, Saito & Ishikawa, 2012). Telomere shortening was further exacerbated with the introduction of dominant negative CTC1 mutants incapable of interacting with DNA Pol‐α, leading to marked heterogeneity in the length of the G‐overhang and a smear of very long telomeres suggestive of telomere hyperextension (Figure 6b).…”

Section: Discussionmentioning

confidence: 95%

CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

Jia

Takasugi

et al. 2018

Aging Cell

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SummaryCoats plus (CP) is a rare autosomal recessive disorder caused by mutations in CTC1, a component of the CST (CTC1, STN1, and TEN1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC1L1142H mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR/Cas9 to engineer this mutation into both alleles of HCT116 and RPE cells to demonstrate that CTC1:STN1 interaction is required to repress telomerase activity. CTC1L1142H interacts poorly with STN1, leading to telomerase‐mediated telomere elongation. Impaired interaction between CTC1L1142H:STN1 and DNA Pol‐α results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol‐α is required to fully repress telomerase activity. CP CTC1 mutants that fail to interact with DNA Pol‐α resulted in loss of C‐strand maintenance and catastrophic telomere shortening. Our findings place the CST complex as an important regulator of both G‐strand extensions by telomerase and C‐strand synthesis by DNA Pol‐α.

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Xenopus laevis Ctc1-Stn1-Ten1 (xCST) Protein Complex Is Involved in Priming DNA Synthesis on Single-stranded DNA Template in Xenopus Egg Extract

Cited by 61 publications

References 37 publications

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

Human Stn1 protects telomere integrity by promoting efficient lagging-strand synthesis at telomeres and mediating C-strand fill-in

MERISTEM DISORGANIZATION1Encodes TEN1, an Essential Telomere Protein That Modulates Telomerase Processivity inArabidopsis

CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

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