Sige Zou

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Papers by Sige Zou

RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals

Nucleic acids research, Jul 1, 2016

DNA Topoisomerases are essential to resolve topological problems during DNA metabolism in all spe... more DNA Topoisomerases are essential to resolve topological problems during DNA metabolism in all species. However, the prevalence and function of RNA topoisomerases remain uncertain. Here, we show that RNA topoisomerase activity is prevalent in Type IA topoisomerases from bacteria, archaea, and eukarya. Moreover, this activity always requires the conserved Type IA core domains and the same catalytic residue used in DNA topoisomerase reaction; however, it does not absolutely require the non-conserved carboxyl-terminal domain (CTD), which is necessary for relaxation reactions of supercoiled DNA. The RNA topoisomerase activity of human Top3β differs from that of Escherichia coli topoisomerase I in that the former but not the latter requires the CTD, indicating that topoisomerases have developed distinct mechanisms during evolution to catalyze RNA topoisomerase reactions. Notably, Top3β proteins from several animals associate with polyribosomes, which are units of mRNA translation, whereas...

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Cytochrome b5 reductase and the control of lipid metabolism and healthspan

npj Aging and Mechanisms of Disease, 2016

Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids,... more Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. A...

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Dietary Restriction and Aging in Drosophila Melanogaster

Calorie Restriction, Aging and Longevity, 2010

Dietary restriction (DR), the reduction of nutrient intake without causing malnutrition, is one e... more Dietary restriction (DR), the reduction of nutrient intake without causing malnutrition, is one environmental intervention that has been shown to extend the life span of a variety of organisms. Drosophila melanogaster is ideally suited for experiments into the biological effects of DR and aging due to its short life span and thorough characterization at the molecular and genetic level. Furthermore,

Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids

Neurobiology of aging, 2012

Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates--are stress-induc... more Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates--are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (A...

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Expression Profile of Aging and Oxidative Stress Response in Drosophila Melanogaster

TheScientificWorldJOURNAL, 2001

The free radical hypothesis of aging suggests that reactive oxygen species accumulated with age c... more The free radical hypothesis of aging suggests that reactive oxygen species accumulated with age cause oxidative damages to molecules, such as nucleic acids, proteins and lipids, and are causally linked to aging and death(1). The regulation of gene expression in aging and its correlation with that in response to oxidative stress, however, is poorly understood. We have used the microarray technique to study the genome-wide expression patterns of aging and oxidative stress response in Drosophila melanogaster. Poly(A) isolated from fly thorax and abdomen was utilized to synthesize fluorescently labeled cDNA. For hybridization to microarrays (2), cDNA from 3-day old flies labeled with Cy3 was co-hybridized with those from 3, 10, 15, 25, 40, or 50 days old flies labeled with Cy5; cDNA from sucrose-fed flies was labeled with Cy3 and co-hybridized with cDNA from 3-hr, 12-hr, 25-hr or 34-hr paraquat-fed flies labeled with Cy5. The microarray data were submitted and stored in the AMAD database designed by J. DeRisi. The expression patterns of all the ESTs were analyzed by the Cluster and Treeview programs (3).

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Sirtuins and Aging

Epigenetics of Aging, 2010

Page 1. Sirtuins and Aging Yuqing Dong and Sige Zou Abstract Sirtuins are a family of highly cons... more

Silent chromatin determines target preference of the Saccharomyces retrotransposon Ty5

Proceedings of the National Academy of Sciences, 1997

The HML and HMR mating loci of Saccharomyces cerevisiae are bound in silent chromatin, which is a... more The HML and HMR mating loci of Saccharomyces cerevisiae are bound in silent chromatin, which is assembled at the flanking E and I transcriptional silencers. The retrotransposon Ty5 preferentially integrates into regions of silent chromatin, and Ty5 insertions near the HMR-E silencer account for ≈2% of total transposition events. Most Ty5 insertions occur within 800 bp on either side of the autonomously replicating consensus sequence within HMR-E . Ty5 target preference is determined by silent chromatin, because integration near HMR-E is abolished in strains with silencer mutations that alleviate transcriptional repression. The recognition of specific DNA sequences per se does not direct integration, rather, it is the protein complex assembled at the silencers. As demonstrated here for Ty5, recognition of specific chromatin domains may be a general mechanism by which retrotransposons and retroviruses determine integration sites.

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Unraveling Regulatory Programs for NF-kappaB, p53 and MicroRNAs in Head and Neck Squamous Cell Carcinoma

PLoS ONE, 2013

In head and neck squamous cell carcinoma (HNSCC), mutations of p53 usually coexist with aberrant ... more In head and neck squamous cell carcinoma (HNSCC), mutations of p53 usually coexist with aberrant activation of NF-kappaB (NF-kB), other transcription factors and microRNAs, which promote tumor pathogenesis. However, how these factors and microRNAs interact to globally modulate gene expression and mediate oncogenesis is not fully understood. We devised a novel bioinformatics method to uncover interactive relationships between transcription factors or microRNAs and genes. This approach is based on matrix decomposition modeling under the joint constraints of sparseness and regulator-target connectivity, and able to integrate gene expression profiling and binding data of regulators. We employed this method to infer the gene regulatory networks in HNSCC. We found that the majority of the predicted p53 targets overlapped with those for NF-kB, suggesting that the two transcription factors exert a concerted modulation on regulatory programs in tumor cells. We further investigated the interrelationships of p53 and NF-kB with five additional transcription factors, AP1, CEBPB, EGR1, SP1 and STAT3, and microRNAs mir21 and mir34ac. The resulting gene networks indicate that interactions among NF-kB, p53, and the two miRNAs likely regulate progression of HNSCC. We experimentally validated our findings by determining expression of the predicted NF-kB and p53 target genes by siRNA knock down, and by examining p53 binding activity on promoters of predicted target genes in the tumor cell lines. Our results elucidating the cross-regulations among NF-kB, p53, and microRNAs provide insights into the complex regulatory mechanisms underlying HNSCC, and shows an efficient approach to inferring gene regulatory programs in biological complex systems.

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Preserved learning and memory following 5-fluorouracil and cyclophosphamide treatment in rats

Pharmacology Biochemistry and Behavior, 2011

Some patients experience enduring cognitive impairment after cancer treatment, a condition termed... more Some patients experience enduring cognitive impairment after cancer treatment, a condition termed "chemofog". Animal models allow assessment of chemotherapy effects on learning and memory per se, independent of changes due to cancer itself or associated health consequences such as depression. The present study examined the long-term learning and memory effects of a chemotherapy cocktail used widely in the treatment of breast cancer, consisting of 5-fluorouracil (5FU) and cyclophosphamide (CYP). Eighty 5-month old male F344 rats received contextual and cued fear conditioning before treatment with saline, or a low or high dose drug cocktail (50 mg/kg CYP and 75 mg/kg 5FU, or 75 mg/kg CYP and 120 mg/kg 5FU, i.p., respectively) every 30 days for 2 months. After a 2-month, no-drug recovery, both long-term retention and new task acquisition in the water maze and 14-unit T-maze were assessed. Neither dose of the CYP/5FU cocktail impaired retrograde fear memory despite marked toxicity documented by enduring weight loss and 50% mortality at the higher dose. Acquisition in the water maze and Stone maze was also normal relative to controls in rats treated with CYP/5FU. The results contribute to a growing literature suggesting that learning and memory mediated by the hippocampus can be relatively resistant to chemotherapy. Future investigation may need to focus on assessments of processing speed, executive function and attention, and the possible interactive contribution of cancer itself and aging to the post-treatment development of cognitive impairment.

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Supplement Timing of Cranberry Extract Plays a Key Role in Promoting Caenorhabditis elegans Healthspan

Nutrients, 2014

Consumption of nutraceuticals is a major and potent dietary intervention for delaying aging. As t... more Consumption of nutraceuticals is a major and potent dietary intervention for delaying aging. As the timing of administration is critical for the efficacy of bioactive compounds in medicine, the effectiveness of nutraceuticals may also be dramatically affected by the timing of supplementation. Cranberry exact (CBE), rich in polyphenols, is consumed as a nutraceutical, and possesses anti-aging properties. Here, we examined the influence of timing on the beneficial effects of CBE supplementation in C. elegans. The prolongevity effect of CBE in different aged worms, young adults, middle-age adults, and aged adults, was determined. Early-start intervention with CBE prolonged the remaining lifespan of worms of different ages more robustly than late-start intervention. The effectiveness of CBE on stress responses and physiological behaviors in different aged worms was also investigated. The early-start intervention prominently promoted motility and resistance to heat shocks and V. cholera infection, especially in aged worms. Together, these findings suggest that the timing of CBE supplementation critically influences its OPEN ACCESS Nutrients 2014, 6 912 beneficial effects on C. elegans lifespan and healthspan. It is of interest to further investigate whether the similar results would occur in humans.

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Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation

Nature Neuroscience, 2013

Topoisomerases are crucial to solve DNA topological problems, but they have not been linked to RN... more Topoisomerases are crucial to solve DNA topological problems, but they have not been linked to RNA metabolism. Here we show that human topoisomerase 3β (Top3β) is an RNA topoisomerase that biochemically and genetically interacts with FMRP, a protein deficient in Fragile X syndrome and known to regulate translation of mRNAs important for neuronal function and autism. Notably, the FMRP-Top3β interaction is abolished by a disease-associated FMRP mutation, suggesting that Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Dietary activators of Sirt1

Molecular and Cellular Endocrinology, 2009

Calorie restriction (CR) is a non-genetic manipulation that reliably results in extended lifespan... more Calorie restriction (CR) is a non-genetic manipulation that reliably results in extended lifespan of several species ranging from yeast to dogs. The lifespan extension effect of CR has been strongly associated with an increased level and activation of the Sir2 histone deacetylase and its mammalian ortholog Sirt1. This association led to the search for potential Sirt1-activating, life-extending molecules. This review briefly outlines the experimental findings on resveratrol and other dietary activators of Sirt1.

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Comparative approaches to facilitate the discovery of prolongevity interventions: Effects of tocopherols on lifespan of three invertebrate species

Mechanisms of Ageing and Development, 2007

Many compounds hold promise for pharmacologic manipulation of aging. However, such claims are dif... more Many compounds hold promise for pharmacologic manipulation of aging. However, such claims are difficult to investigate due to time and budget constraints. Here, we took a comparative approach, using short-lived invertebrate species, to directly test the effects of two tocopherols (vitamin E) on longevity. γ-tocopherol represents the most abundant tocopherol in the Western diet, while αtocopherol is selectively enriched in human plasma. Both isoforms demonstrate antioxidant activity and are proposed to have anti-aging activities. We compared the effects of αand γ-tocopherol supplementation on lifespan in three invertebrate species. γ-, but not α-, tocopherol slightly extended lifespan in nematodes, but neither significantly affected lifespan in two fly species. This study shows that a comparative approach, utilizing multiple invertebrate species, can increase the robustness of invertebrate-based pilot screens for prolongevity interventions. Pharmacological and nutritional approaches to retard aging and increase longevity have been proposed , Ingram et al., 2006. Large-scale screens are being considered for a number of model organisms to accelerate discovery of compounds with the greatest potential for extending lifespan , Gill et al., 2003, Sampayo et al., 2003. One class of compounds with potentially beneficial effects on aging are the tocopherol isomers found in Vitamin E and which are found naturally in plant oils . Vitamin E is a mixture of several related tocopherol and tocotrienol isomers, including the αand γ-tocopherols. The Western diet is enriched in γ-tocopherol, but α-tocopherol is selectively retained in human plasma (Jiang et al., 2001, Tucker and. Both tocopherols are derived from fatty acids and exist within membranes, where they affect membrane fluidity and can act as antioxidants. The high antioxidant capacity of vitamin E makes it a candidate for a prolongevity therapy, since aging is correlated with increased oxidative stress in cells (Ames et al.,

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