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NAD AND telomerase

Erica J Polleys, Alison A Bertuch
The Saccharomyces cerevisiae Iml1 complex inhibits TORC1 signaling and SEACAT antagonizes the Iml1 complex. Conditions in which SEACAT functions to inhibit Iml1 and, hence, TORC1 signaling, remain largely unknown. The SEACAT member Sea3 was linked previously to telomere maintenance and DNA repair via genome-wide genetic and physical interaction studies. Therefore, we questioned whether Sea3 functioned through TORC1 to influence these pathways. Deletion of SEA3 delayed the emergence of telomerase-independent survivors that use break-induced replication (BIR) to maintain their telomeres...
July 2015: G3: Genes—Genomes—Genetics
Maria Luigia De Bonis, Sagrario Ortega, Maria A Blasco
The NAD-dependent deacetylase SIRT1 is involved in chromatin silencing and genome stability. Elevated SIRT1 levels in embryonic stem cells also suggest a role for SIRT1 in pluripotency. Murine SIRT1 attenuates telomere attrition in vivo and is recruited at telomeres in induced pluripotent stem cells (iPSCs). Because telomere elongation is an iPSC hallmark, we set out to study the role of SIRT1 in pluripotency in the setting of murine embryonic fibroblasts reprogramming into iPSCs. We find that SIRT1 is required for efficient postreprogramming telomere elongation, and that this effect is mediated by a c-MYC-dependent regulation of the mTert gene...
May 6, 2014: Stem Cell Reports
Huiqiang Chen, Xianbao Liu, Wei Zhu, Han Chen, Xinyang Hu, Zhi Jiang, Yinchuan Xu, Lihan Wang, Yu Zhou, Panpan Chen, Na Zhang, Dexing Hu, Ling Zhang, Yaping Wang, Qiyuan Xu, Rongrong Wu, Hong Yu, Jian'an Wang
Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence...
2014: Frontiers in Aging Neuroscience
Julio Morales, Longshan Li, Farjana J Fattah, Ying Dong, Erik A Bey, Malina Patel, Jinming Gao, David A Boothman
Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition...
2014: Critical Reviews in Eukaryotic Gene Expression
Bin Zhang, Juan Chen, Alfred S L Cheng, Ben C B Ko
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that is implicated in plethora of biological processes, including metabolism, aging, stress response, and tumorigenesis. Telomerase (TERT) is essential for telomere maintenance. Activation of TERT is considered a crucial step in tumorigenesis, and therefore it is a potential therapeutic target against cancer. We have recently found that SIRT1 expression is highly elevated in hepatocellular carcinoma, and the depletion of SIRT1 leads to substantial reduction in TERT mRNA and protein expression...
2014: PloS One
Yana V Miteva, Ileana M Cristea
Sirtuin 6 (SIRT6), a member of the mammalian sirtuin family, is a nuclear deacetylase with substrate-specific NAD(+)-dependent activity. SIRT6 has emerged as a critical regulator of diverse processes, including DNA repair, gene expression, telomere maintenance, and metabolism. However, our knowledge regarding its interactions and regulation remains limited. Here, we present a comprehensive proteomics-based analysis of SIRT6 protein interactions and their dependence on SIRT6 catalytic activity. We also identify evolutionarily conserved SIRT6 phosphorylations, including four within a proline-rich disordered region, and show that the conserved S338 phosphorylation can modulate selected SIRT6 interactions...
January 2014: Molecular & Cellular Proteomics: MCP
Craig Nicholls, Alexander Ruvantha Pinto, He Li, Ling Li, Lihui Wang, Richard Simpson, Jun-Ping Liu
Oxidative stress regulates telomere homeostasis and cellular aging by unclear mechanisms. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a key mediator of many oxidative stress responses, involving GAPDH nuclear translocation and induction of cell death. We report here that GAPDH interacts with the telomerase RNA component (TERC), inhibits telomerase activity, and induces telomere shortening and breast cancer cell senescence. The Rossmann fold containing NAD(+) binding region on GAPDH is responsible for the interaction with TERC, whereas a lysine residue in the GAPDH catalytic domain is required for inhibiting telomerase activity and disrupting telomere maintenance...
August 14, 2012: Proceedings of the National Academy of Sciences of the United States of America
Fumiaki Uchiumi, Takeshi Watanabe, Shin Hasegawa, Taisuke Hoshi, Yoshikazu Higami, Sei-ichi Tanuma
Various protein factors, including telomerase and WRN helicase, are involved in telomere maintenance. Resveratrol (Rsv), a polyphenol that extends the lifespan of diverse species is an activator of SIRT1, a NAD(+) dependent deacetylating enzyme in mammalian cells. Here, we examined the changes in gene expressions and promoter activities of WRN helicase and telomerase after Rsv treatment. This treatment increased the amount of WRN transcript and protein product by activating its promoter and telomerase promoter activity and gene expression...
February 2011: Current Aging Science
Nabora Soledad Reyes de Mochel, Scott Seronello, Shelley Hsiuying Wang, Chieri Ito, Jasper Xi Zheng, T Jake Liang, J David Lambeth, Jinah Choi
UNLABELLED: Oxidative stress has been identified as a key mechanism of hepatitis C virus (HCV)-induced pathogenesis. Studies have suggested that HCV increases the generation of hydroxyl radical and peroxynitrite close to the cell nucleus, inflicting DNA damage, but the source of reactive oxygen species (ROS) remains incompletely characterized. We hypothesized that HCV increases the generation of superoxide and hydrogen peroxide close to the hepatocyte nucleus and that this source of ROS is reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase 4 (Nox4)...
July 2010: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Amanda Greenall, Guiyuan Lei, Daniel C Swan, Katherine James, Liming Wang, Heiko Peters, Anil Wipat, Darren J Wilkinson, David Lydall
BACKGROUND: Telomeres prevent the ends of eukaryotic chromosomes from being recognized as damaged DNA and protect against cancer and ageing. When telomere structure is perturbed, a co-ordinated series of events promote arrest of the cell cycle so that cells carrying damaged telomeres do not divide. In order to better understand the eukaryotic response to telomere damage, budding yeast strains harboring a temperature sensitive allele of an essential telomere capping gene (cdc13-1) were subjected to a transcriptomic study...
2008: Genome Biology
Eriko Michishita, Ronald A McCord, Elisabeth Berber, Mitomu Kioi, Hesed Padilla-Nash, Mara Damian, Peggie Cheung, Rika Kusumoto, Tiara L A Kawahara, J Carl Barrett, Howard Y Chang, Vilhelm A Bohr, Thomas Ried, Or Gozani, Katrin F Chua
The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin...
March 27, 2008: Nature
Swami R Narala, Richard C Allsopp, Trystan B Wells, Guanglei Zhang, Prerna Prasad, Matthew J Coussens, Derrick J Rossi, Irving L Weissman, Homayoun Vaziri
SIRT1, the mammalian homolog of SIR2 in Saccharomyces cerevisiae, is an NAD-dependent deacetylase implicated in regulation of lifespan. By designing effective short hairpin RNAs and a silent shRNA-resistant mutant SIRT1 in a genetically defined system, we show that efficient inhibition of SIRT1 in telomerase-immortalized human cells enhanced cell growth under normal and nutrient limiting conditions. Hematopoietic stem cells obtained from SIRT1-deficient mice also showed increased growth capacity and decreased dependency on growth factors...
March 2008: Molecular Biology of the Cell
Utpal Ghosh, Nilanjana Das, Nitai P Bhattacharyya
Inhibitors of poly(ADP-ribose) polymerase (PARP) have been shown to reduce the telomerase activity in cultured cells. To find out the specific member of the PARP family, which participates in the regulation of telomerase activity, in the present investigation, we knocked down the PARP-1 gene by siRNA in HeLa cells and studied the telomerase activity. Reduction of expression of PARP-1 by siRNA increased cellular NAD(+) level and decreased general poly(ADP-ribosyl)ation of proteins. Telomerase activity decreased in cells with knocked down PARP-1 gene...
February 3, 2007: Mutation Research
Utpal Ghosh, Nitai P Bhattacharyya
To test the role of poly(ADP-ribose) polymerase on the telomerase activity, we determined the telomerase activity in leukemic cells K562 treated with benzamide and 4-amino 1,8 naphthalimide (NAP), the inhibitors of PARP. We observed that both the agents inhibited telomerase activity in a dose-dependent manner. The doses of benzamide and NAP that inhibited telomerase activity to 50% of untreated control cells were 10.7 +/- 0.6 mm and 200 +/- 7 microm, respectively. Benzamide treatment (10 mm) inhibited telomerase activity in a time-dependent manner...
August 2005: FEBS Journal
Sho Takagi, Yoshitaka Kinouchi, Nobuo Hiwatashi, Masashi Hirai, Susumu Suzuki, Seiichi Takahashi, Kenichi Negoro, Nobuya Obana, Tooru Shimosegawa
AIM: The aim of this study was to examine whether and relationships could be found among polymorphism of the NQO1 gene, telomere length and telomerase activity in colorectal cancers. MATERIALS AND METHODS: Fifty-one invasive colorectal cancers were studied. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was undergone to detect mutation of the NQO1 gene. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications...
September 2002: Anticancer Research
J Yui, C P Chiu, P M Lansdorp
Telomerase is a ribonucleoprotein polymerase that synthesizes telomeric repeats onto the 3' ends of eukaryotic chromosomes. Activation of telomerase may prevent telomeric shortening and correlates with cell immortality in the germline and certain tumor cells. Candidate hematopoietic stem cells (HSC) from adult bone marrow express low levels of telomerase, which is upregulated with proliferation and/or differentiation. To address this issue, we stimulated purified candidate HSC from human adult bone marrow with stem cell factor (SCF), interleukin-3 (IL-3), and Flt3-ligand (FL)...
May 1, 1998: Blood
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