RPA-like Mammalian Ctc1-Stn1-Ten1 Complex Binds to Single-Stranded DNA and Protects Telomeres Independently of the Pot1 Pathway

Miyake, Yasuyuki; Nakamura, Michio; Nabetani, Akira; Shimamura, Shintaro; Tamura, Miki; Yonehara, Shin; Saito, Motoki; Ishikawa, Fuyuki

doi:10.1016/j.molcel.2009.08.009

Cited by 327 publications

(517 citation statements)

References 34 publications

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“…Genes encoding proteins with functions in spermatogenesis (Supplementary Figure S9) and DNA damage response (Supplementary Figure S10) were selected, and their differential expression was confirmed by qPCR. DNA damage related genes ( Nbn, Rif1, Sun1, Ctc1 ) are also known to be involved in the regulation of telomere function (81–85). To determine whether telomere length is altered in ATZ-lineage males, we analyzed the average telomere length ratio (ATLR) in genomic DNA from the testes and liver using recently developed qPCR approach (86).…”

Section: Resultsmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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The epigenetic events imposed during germline reprogramming and affected by harmful exposure can be inherited and transferred to subsequent generations via gametes inheritance. In this study, we examine the transgenerational effects promoted by widely used herbicide atrazine (ATZ). We exposed pregnant outbred CD1 female mice and the male progeny was crossed for three generations with untreated females. We demonstrate here that exposure to ATZ affects meiosis, spermiogenesis and reduces the spermatozoa number in the third generation (F3) male mice. We suggest that changes in testis cell types originate from modified transcriptional network in undifferentiated spermatogonia. Importantly, exposure to ATZ dramatically increases the number of transcripts with novel transcription initiation sites, spliced variants and alternative polyadenylation sites. We found the global decrease in H3K4me3 occupancy in the third generation males. The regions with altered H3K4me3 occupancy in F3 ATZ-derived males correspond to altered H3K4me3 occupancy of F1 generation and 74% of changed peaks in F3 generation are associated with enhancers. The regions with altered H3K4me3 occupancy are enriched in SP family and WT1 transcription factor binding sites. Our data suggest that the embryonic exposure to ATZ affects the development and the changes induced by ATZ are transferred up to three generations.

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Section: Resultsmentioning

confidence: 99%

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

et al. 2016

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“…Recently, it has been shown that CTC1 interacts with STN1 and TEN1 to form the mammalian homolog of the yeast hetero trimeric Cdc13 Stn1 Ten1 (CST) telomeric capping complex 13,14 . Consequently, we also undertook Sanger sequencing of OBFC1 (STN1) and TEN1 in our collection of individuals with Labrune syndrome and in the proband with Coats plus in whom we identified no CTC1 mutations.…”

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confidence: 99%

“…Because of rapid evolutionary divergence, the human CST complex was only defined recently 13,14 . This led to the recognition that mammalian l e t t e r s CTC1 is identical to one subunit of α accessory factor (AAF 132), whereas a second subunit of AAF (AAF 44, also known as OBFC1) corresponds to mammalian STN1 (ref.…”

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confidence: 99%

“…However, the CST complex only partially localizes to telomeres and binds to ssDNA in a sequence independent manner (through the oligonucleotide/oligosaccharide binding (OB) fold domains predicted to be present in all three subunits) 13,14 . Of note, knockdown of CTC1 in human cells resulted in an increase in the number of γH2AX foci not confined to telomeres 13 .…”

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Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Anderson¹,

Kasher²,

Mayer³

et al. 2012

Nat Genet

247

237

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Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity

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“…These proteins include the evolutionarily conserved CTC1: STN1: TEN1 (CST) complex. CTC1 and STN1 were originally discovered as proteins that stimulate DNA Pol‐α: primase activity, suggesting an essential role for CST in DNA replication (Casteel et al., 2009; Miyake et al., 2009; Surovtseva et al., 2009). Targeted deletion of CTC1 in the mouse, as well as depletion of individual CST components in human cells, all results in telomere replication defects and global telomere attrition, suggesting that the CST complex is required for multiple steps of telomere replication (Feng, Hsu, Kasbek, Chaiken & Price, 2017; Gu et al., 2012; Wu, Takai & de Lange, 2012).…”

Section: Introductionmentioning

confidence: 99%

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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RPA-like Mammalian Ctc1-Stn1-Ten1 Complex Binds to Single-Stranded DNA and Protects Telomeres Independently of the Pot1 Pathway

Cited by 327 publications

References 34 publications

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Exposure to the widely used herbicide atrazine results in deregulation of global tissue-specific RNA transcription in the third generation and is associated with a global decrease of histone trimethylation in mice

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

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

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