The telomerase reverse transcriptase: components and regulation

Nugent, Constance I.; Lundblad, Victoria

doi:10.1101/gad.12.8.1073

Cited by 412 publications

(251 citation statements)

References 110 publications

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“…The core of this enzyme from all species is minimally composed of a protein-catalytic subunit and a single-stranded RNA called TERT and TR, respectively (Nugent and Lundblad, 1998;Collins, 2006). The expression of TERT has been demonstrated as a rate-limiting step in human cellular telomerase activation, and it is suppressed by multiple tumor-suppressor pathways in normal human cells but is activated by numerous oncogenic transcription factors (Meyerson et al, 1997;Liu et al, 2000;Cong et al, 2002;Lin and Elledge, 2003;Goueli and Janknecht, 2004).…”

Section: Introductionmentioning

confidence: 99%

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Zhang

Dong

H.³

et al. 2011

Oncogene

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Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the downregulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies.

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Section: Introductionmentioning

confidence: 99%

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Zhang

Dong

H.³

et al. 2011

Oncogene

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“…[6][7][8] Telomeres are maintained by a specialized reverse transcriptase, called the ribonucleoprotein telomerase, which is composed of a ubiquitously expressed RNA subunit, telomerase RNA component (TERC), 9 and a protein catalytic subunit, telomerase reverse transcriptase (TERT), whose expression is highly regulated. 10,11 Telomere maintenance of the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Supporting this hypothesis, initial surveys of human cell lines and tissue specimens with a sensitive biochemical assay for the telomerase activity (telomere repeat amplification protocol (TRAP)) demonstrated readily detectable telomerase activity in the majority of cancer cell lines and tumors.…”

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confidence: 99%

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment

et al. 2005

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Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoterbased CRAds may be a potentially effective strategy for cancer treatment.

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“…However, these proteins are not required for the in vitro activity of telomerase (Cohn and Blackburn, 1995;Lingner et al, 1997b). Based on this observation, Est1p and Est3p have been proposed to play essential regulatory roles in vivo (Nugent and Lundblad, 1998). Indeed, Est1p directly interacts with Cdc13p, a protein that binds single-stranded telomeric DNA, and this interaction recruits or activates telomerase at the telomere (Evans and Lundblad, 1999;Qi and Zakian, 2000;Pennock et al, 2001;Taggart et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

N-terminal Domain of Yeast Telomerase Reverse Transcriptase: Recruitment of Est3p to the Telomerase Complex

Friedman

Heit

Long

et al. 2003

MBoC

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Telomerase is a reverse transcriptase that maintains chromosome ends. The N-terminal half of the catalytic protein subunit (TERT) contains three functional domains (I, II, and III) that are conserved among TERTs but not found in other reverse transcriptases. Guided by an amino acid sequence alignment of nine TERT proteins, mutations were introduced into yeast TERT (Est2p). In support of the proposed alignment, mutation of virtually all conserved residues resulted in loss-of-function or temperature sensitivity, accompanied by telomere shortening. Overexpression of telomerase component Est3p led to allele-specific suppression of the temperature-sensitive mutations in region I, suggesting that Est3p interacts with this protein domain. As predicted by the genetic results, a lethal mutation in region I resulted in loss of Est3p from the telomerase complex. We conclude that Est2p region I is required for the recruitment of Est3p to yeast telomerase. Given the phylogenetic conservation of region I of TERT, this protein domain may provide the equivalent function in all telomerases.

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The telomerase reverse transcriptase: components and regulation

Cited by 412 publications

References 110 publications

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment

N-terminal Domain of Yeast Telomerase Reverse Transcriptase: Recruitment of Est3p to the Telomerase Complex

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