Telomerase Unplugged

Cristofari, Gaël; Sikora, Katarzyna; Lingner, Joachim

doi:10.1021/cb700037c

Cited by 15 publications

(10 citation statements)

References 26 publications

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“…The results presented here support the emerging view that certain shelterin components act as both negative and positive regulators of telomerase function (14,40,48,52). While collectively the shelterin proteins inhibit telomerase-telomere interactions, evidence indicates that particular telomere-associated proteins can also interact with and recruit telomerase.…”

Section: Discussionsupporting

confidence: 83%

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TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres In Vivo

Abreu

Aritonovska

Reichenbach

et al. 2010

Molecular and Cellular Biology

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217

231

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Recruitment to telomeres is a pivotal step in the function and regulation of human telomerase; however, the molecular basis for recruitment is not known. Here, we have directly investigated the process of telomerase recruitment via fluorescence in situ hybridization (FISH) and chromatin immunoprecipitation (ChIP). We find that depletion of two components of the shelterin complex that is found at telomeres-TPP1 and the protein that tethers TPP1 to the complex, TIN2-results in a loss of telomerase recruitment. On the other hand, we find that the majority of the observed telomerase association with telomeres does not require POT1, the shelterin protein that links TPP1 to the single-stranded region of the telomere. Deletion of the oligonucleotide/oligosaccharide binding fold (OB-fold) of TPP1 disrupts telomerase recruitment. In addition, while loss of TPP1 results in the appearance of DNA damage factors at telomeres, the DNA damage response per se does not account for the telomerase recruitment defect observed in the absence of TPP1. Our findings indicate that TIN2-anchored TPP1 plays a major role in the recruitment of telomerase to telomeres in human cells and that recruitment does not depend on POT1 or interaction of the shelterin complex with the single-stranded region of the telomere.

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Section: Discussionsupporting

confidence: 83%

“…TPP1 could theoretically function in telomerase recruitment specifically when bound to the single-stranded 3Ј region of the telomere via POT1 (14,16,38,51) (Fig. 1A).…”

Section: Discussionmentioning

confidence: 99%

TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres In Vivo

Abreu

Aritonovska

Reichenbach

et al. 2010

Molecular and Cellular Biology

Self Cite

217

231

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“…POT1 directly binds to the telomeric DNA primer while TPP1 simultaneously binds to POT1 and TERT. Thus the POT1–TPP1 complex holds the DNA primer in close proximity to telomerase, delaying primer release from the enzyme, and enhancing repeat addition processivity [31]. The structural elements within the TR and TERT which increase processivity are discussed further in the following sections.…”

Section: Telomerase Enzymatic Propertiesmentioning

confidence: 99%

It all comes together at the ends: Telomerase structure, function, and biogenesis

Podlevsky

Chen

2012

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

124

110

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Telomerase is a reverse transcriptase specialized in the addition of telomeric DNA repeats onto the ends of chromosomes. Telomere extension offsets the loss of telomeric repeats from the failure of DNA polymerases to fully replicate linear chromosome ends. Telomerase functions as a ribonucleoprotein, requiring an integral telomerase RNA (TR) component, in addition to the catalytic telomerase reverse transcriptase (TERT). Extensive studies have identified numerous structural and functional features within the TR and TERT essential for activity. A number of accessory proteins have also been identified with various functions in enzyme biogenesis, localization, and regulation. Understanding the molecular mechanism of telomerase function has significance for the development of therapies for telomere-mediated disorders and cancer. Here we review telomerase structural and functional features, and the techniques for assessing telomerase dysfunction.

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“…Species-specific determinants that are present in hTERT, but lacking in mTERT, or altered in the mTERT-hTR and chimeric TERT-hTR complexes, might be responsible for recruiting the telomerase complex to the shortest telomeres. Many cellular proteins affect the function of the telomerase holoenzyme (Cristofari et al, 2007). Proteins that modulate telomerase activity, processivity and/or recruitment to telomeres include TPP1, POT1, Pif1, EST1p and PinX1 (Snow et al, 2003;Wang et al, 2007;Xin et al, 2007;Zhang et al, 2006;Zhou and Lu, 2001).…”

Section: Lack Of Mtert Recruitment To and Elongation Of The Shortest mentioning

confidence: 99%

Telomeric function of mammalian telomerases at short telomeres

Fakhoury

Marie-Egyptienne

Londoño-Vallejo

et al. 2010

Journal of Cell Science

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SummaryTelomerase synthesizes telomeric sequences and is minimally composed of a reverse transcriptase (RT) known as TERT and an RNA known as TR. We reconstituted heterologous mouse (m) and human (h) TERT-TR complexes and chimeric mTERT-hTERT-hTR complexes in vitro and in immortalized human alternative lengthening of telomere (ALT) cells. Our data suggest that species-specific determinants of activity, processivity and telomere function map not only to the TR but also to the TERT component. The presence of hTERT-hTR, but not heterologous TERT-TR complexes or chimeric mTERT-hTERT-hTR complexes, significantly reduced the percentage of chromosomes without telomeric signals in ALT cells. Moreover, heterologous and chimeric complexes were defective in recruitment to telomeres. Our results suggest a requirement for several hTERT domains and interaction with multiple proteins for proper recruitment of telomerase to the shortest telomeres in human ALT cells. Late-passage mTERT -/-mouse embryonic stem (ES) cells ectopically expressing hTERT or mTERT harboured fewer chromosome ends without telomeric signals and end-to-end fusions than typically observed in late-passage mTERT -/-ES cells. The ability of hTERT to function at mouse telomeres and the inability of mTERT to function at human telomeres suggest that mechanisms regulating the recruitment and activity of hTERT at mouse telomeres might be less stringent than the mechanisms regulating mTERT at human telomeres.

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Telomerase Unplugged

Cited by 15 publications

References 26 publications

TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres In Vivo

TIN2-Tethered TPP1 Recruits Human Telomerase to Telomeres In Vivo

It all comes together at the ends: Telomerase structure, function, and biogenesis

Telomeric function of mammalian telomerases at short telomeres

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