Regulating telomere length from the inside out: the replication fork model

Greider, Carol W.

doi:10.1101/gad.280578.116

Cited by 73 publications

(70 citation statements)

References 111 publications

(105 reference statements)

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“…This catastrophic telomere shortening phenotype is reminiscent of the dramatic loss of telomere sequences observed in CTC1 null mice (Gu et al., 2012). Our data support a recent model of telomere maintenance linking DNA replication to telomere length regulation, with the CST complex regulating both G‐strand extension by telomerase and C‐strand fill‐in by DNA pol‐α (Greider, 2016). …”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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

Jia

Takasugi

et al. 2018

Aging Cell

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“…Shelterin also has a role in the regulation of telomerase-mediated telomere length maintenance (reviewed in REF. 184). Several shelterin subunits are negative regulators of telomere length, suggesting that shelterin subunits ‘count’ telomeric repeats to regulate telomerase activity and limit telomere length as part of a cis -acting negative-feedback loop (reviewed in REF.…”

Section: Figurementioning

confidence: 99%

Telomeres in cancer: tumour suppression and genome instability

Maciejowski

Lange

2017

Nat Rev Mol Cell Biol

587

495

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The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.

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“…Endogenous telomerase action at telomeres is restricted to the cell cycle S phase (108, 122, 148). This control of telomerase action does not derive from regulated assembly of the RNP catalytic core, because telomerase activity is present in cell extracts at all stages of the cell cycle in all examined model systems.…”

Section: Cellular Ribonucleoprotein Assembly and Action At Telomeresmentioning

confidence: 99%

Telomerase Mechanism of Telomere Synthesis

Upton

Vogan

et al. 2017

Annu. Rev. Biochem.

192

186

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Telomerase is the essential reverse transcriptase required for linear chromosome maintenance in most eukaryotes. Telomerase supplements the tandem array of simple-sequence repeats at chromosome ends to compensate for the DNA erosion inherent in genome replication. The template for telomerase reverse transcriptase is within the RNA subunit of the ribonucleoprotein complex, which in cells contains additional telomerase holoenzyme proteins that assemble the active ribonucleoprotein and promote its function at telomeres. Telomerase is distinct among polymerases in its reiterative reuse of an internal template. The template is precisely defined, processively copied, and regenerated by release of single-stranded product DNA. New specificities of nucleic acid handling that underlie the catalytic cycle of repeat synthesis derive from both active site specialization and new motif elaborations in protein and RNA subunits. Studies of telomerase provide unique insights into cellular requirements for genome stability, tissue renewal, and tumorigenesis as well as new perspectives on dynamic ribonucleoprotein machines.

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Regulating telomere length from the inside out: the replication fork model

Cited by 73 publications

References 111 publications

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

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

Telomeres in cancer: tumour suppression and genome instability

Telomerase Mechanism of Telomere Synthesis

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