Telomerase caught in the act

Gallardo, Franck; Laterreur, Nancy; Wellinger, Raymund J.; Chartrand, Pascal

doi:10.4161/rna.21498

Cited by 4 publications

(2 citation statements)

References 37 publications

(37 reference statements)

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“…Nuclear import of telomerase holoenzyme is mediated by mRNA transport defective protein 10 (Mtr10) and karyopherin protein 122 (Kap122), enhanced by Ku–TLC1 interaction (87). Once in the nucleoplasm, telomerase can be recruited to telomeres (105, 108). Quantitative imaging of TLC1 in cells suggests that each TLC1–monomer RNP diffuses independently through the nucleoplasm until encountering a replicated telomere (109, 110).…”

Section: Cellular Ribonucleoprotein Assembly and Action At Telomeresmentioning

confidence: 99%

“…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%

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Telomerase Mechanism of Telomere Synthesis

Upton

Vogan

et al. 2017

Annu. Rev. Biochem.

187

191

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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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Section: Cellular Ribonucleoprotein Assembly and Action At Telomeresmentioning

confidence: 99%

Section: Cellular Ribonucleoprotein Assembly and Action At Telomeresmentioning

confidence: 99%

Telomerase Mechanism of Telomere Synthesis

Upton

Vogan

et al. 2017

Annu. Rev. Biochem.

187

191

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Dynamics of Human Telomerase Holoenzyme Assembly and Subunit Exchange across the Cell Cycle

Vogan

Collins

2015

Journal of Biological Chemistry

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Background: Telomerase elongation of chromosome ends is restricted within the cell cycle. Results: A human telomerase holoenzyme subunit mediating Cajal body and telomere localization disassembles reversibly from the RNP catalytic core in each cell cycle. Conclusion: Telomerase holoenzyme assembly and disassembly are favored at distinct stages of the cell cycle. Significance: Human telomerase is relicensed for telomere synthesis in G 1 .

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Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation ofOBFC1

Cardinale

Cantalupo

Lasorsa

et al. 2021

Human Molecular Genetics

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The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.

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Telomerase caught in the act

Cited by 4 publications

References 37 publications

Telomerase Mechanism of Telomere Synthesis

Telomerase Mechanism of Telomere Synthesis

Dynamics of Human Telomerase Holoenzyme Assembly and Subunit Exchange across the Cell Cycle

Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation ofOBFC1

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