Structural Basis of Selective Ubiquitination of TRF1 by SCFFbx4

Zeng, Zhixiong; Wang, Wei; Yang, Yuting; Chen, Yong; Yang, Xiaomei; Diehl, J. Alan; Liu, Xuedong; Lei, Ming

doi:10.1016/j.devcel.2010.01.007

Cited by 59 publications

(86 citation statements)

References 56 publications

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“…Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination [78]. Now, researchers have discovered that a third protein, TIN2, can step in and override Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it [78]. The data demonstrate that recognition of TRF1 by SCF(Fbx4) is regulated by this telomere protein, TIN2.…”

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 97%

“…Strikingly, this atypical GTPase domain of Fbx4 binds to a globular domain of TRF1 through an intermolecular β sheet instead of recognizing short peptides/degrons as often seen in other F-box protein-substrate complexes. Importantly, mutations in this interface abrogate Fbx4-dependent TRF1 binding and ubiquitination [78]. Now, researchers have discovered that a third protein, TIN2, can step in and override Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it [78].…”

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 99%

“…As such, TRF1 levels are regulated by ubiquitin-dependent proteolysis via an SCF E3 ligase, where Fbx4 contributes to substrate specification. The crystal structure of the Fbx4-TRF1 complex at 2.4 Å resolution has been discovered [78]. Fbx4 contains an unusual substrate-binding domain that adopts a small GTPase fold.…”

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 99%

“…The researchers are now looking at peptides that mimic TIN2's binding to TRF1 in order to block Fbx4. The work is still in preliminary stages and no new therapies are being tested in patients [78].…”

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 99%

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Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

Babizhayev¹,

Vishnyakova

Yegorov

2014

Journal of Basic and Clinical Physiology and Pharmacology

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It has been documented that telomere-associated cellular senescence may contribute to certain age-related disorders, and telomere length (TL) may be an informative biomarker of healthy aging. Hormone-brain-aging behaviormodulated telomere dynamics and changes in telomerase activity are consistent elements of cellular alterations associated with changes in proliferative state, and these processes are consequently considered as the new therapeutic drug targets for physiological control with advanced drug delivery and nutritional formulations. We raise and support a therapeutic concept of using nonhydrolyzed forms of naturally occurring neuron-specific imidazole dipeptide-based compounds carnosine and carcinine, making it clinically possible that slowing down the rate of telomere shortening could slow down the human aging process in specific tissues where proliferative senescence is known to occur, with the demonstrated evidence of telomere shortening that appeared to be a hallmark of oxidative stress and disease. Carnosine released from skeletal muscle during exercise may be transported into the hypothalamic tuberomammillary nucleus (TMN) histamine neurons and hydrolyzed. The resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and hormone-like antiaging physiological function. The preliminary longitudinal studies of elderly individuals suggest that longer telomeres are associated with better survival, and an advanced oral nutritional support with nonhydrolyzed carnosine (or carcinine and patented compositions thereof) is a useful therapeutic tool for a critical TL maintenance that may fundamentally be applied in the treatment of age-related sight-threatening eye disorders, prolonged life expectancy, increased survival and chronological age of an organism in health control, smoking behavior, and disease."Our pleasures were simple-they included survival." -Dwight D. Eisenhower, 34th President of the United States, 1953States, -1961

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Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 97%

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 99%

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 99%

Section: Tl and Cellular Aging: Olovnikov's Predictionmentioning

confidence: 99%

See 2 more Smart Citations

Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

Babizhayev¹,

Vishnyakova

Yegorov

2014

Journal of Basic and Clinical Physiology and Pharmacology

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“…Although clinical therapy trials in advanced cancers are only just beginning to target telomerase activity, there are many other genes involved in regulation of telomere function and many cellular pathways that can indirectly affect it (e.g., DNA repair pathways). There are a number of telomere maintenance genes encoding telomerase components (e.g., hTERT and hTERC) and telomere-protective proteins (e.g., TIN2, TRF1, and TRF2) which may lead to the discovery of targets for cancer interception (45).…”

Section: Cancer/ Therapymentioning

confidence: 99%

Cancer Interception

Blackburn

2011

Cancer Prevention Research

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A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787-92. Ó2011 AACR.

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NEDD8 ultimate buster‐1 regulates the abundance of TRF1 at telomeres by promoting its proteasomal degradation

2016

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The human telomeric protein TRF1 negatively regulates telomere length by inhibiting the access of telomerase to telomeres. Here, we describe a novel function of NEDD8 ultimate buster-1 (NUB1) for regulating the levels of TRF1 at telomeres. NUB1 is a NEDD8-interacting protein, which down-regulates the NEDD8 conjugation system. We showed that NUB1 physically interacts with TRF1 and promotes its degradation by the proteasome in the absence of NEDD8 conjugation. We also demonstrated that TRF1 is conjugated to NEDD8, and that neddylated TRF1 is targeted to the proteasome for degradation in a NUB1-dependent manner. These data suggest that NUB1 participates in telomere maintenance by regulating the levels of TRF1 at telomeres through both NEDD8-dependent and NEDD8-independent pathways.

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Structural Basis of Selective Ubiquitination of TRF1 by SCFFbx4

Cited by 59 publications

References 56 publications

Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

Cancer Interception

NEDD8 ultimate buster‐1 regulates the abundance of TRF1 at telomeres by promoting its proteasomal degradation

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