Selenoprotein H Suppresses Cellular Senescence through Genome Maintenance and Redox Regulation

Wu, Ryan T.Y.; Cao, Lei; Chen, Benjamin P.C.; Cheng, Wen Po

doi:10.1074/jbc.m114.611970

Cited by 42 publications

(25 citation statements)

References 79 publications

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“…Thus, SelH appears to be a sensor of oxidative stress in nucleus, where it may play a dual role in redox maintenance as an antioxidant and regulation of gene expression as a transactivator. Such diverse dealings of SelH in genome maintenance and redox regulation is consistent with our recent functional analyses demonstrating a role of this selenoprotein in the protection against replicative senescence in a manner depending on ATM, p53, and reactive oxygen species .…”

Section: Nuclear Selenoproteins and Functionssupporting

confidence: 90%

“…In mammals, SelH mRNA expression is high during embryogenesis, in certain tissues such as brain, thymus, testes and uterus in mice, and in some human cancerous cells such as colorectal HCT116 and prostate LNCaP cells . The expression of SelH mRNA can be upregulated after binding of metal transcription factor‐1 to its metal response element and upon cellular exposure to H 2 O 2 . Thus, SelH appears to be a sensor of oxidative stress in nucleus, where it may play a dual role in redox maintenance as an antioxidant and regulation of gene expression as a transactivator.…”

Section: Nuclear Selenoproteins and Functionsmentioning

confidence: 99%

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Nuclear selenoproteins and genome maintenance

Zhang

Zhu

et al. 2015

IUBMB Life

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Selenium is an essential metalloid required for the expression of selenoproteins. While cells are constantly challenged by clastogens of endogenous and exogenous origins, genome integrity is maintained by direct repair of DNA damage, redox balance, and epigenetic regulation. To date, only five selenoproteins are experimentally demonstrated to reside in nucleus, exclusively or partially, including selenoprotein H, methionine-R-sulfoxide reductase 1, glutathione peroxidase-4, thioredoxin reductase-1, and thioredoxin glutathione reductase. All these five selenoproteins have demonstrated or potential roles in redox regulation and genome maintenance. Selenoprotein H is known to transactivate the expression of a couple of genes against oxidative stress. The thioredoxin reductase-1b isoform delivers estrogen receptor-a and -b to the nucleus. Nuclear glutathione peroxidase-4 epigenetically and globally inhibits gene expression through the maintenance of chromatin compactness in testes. Continued studies on how these and additional nuclear selenoproteins regulate genome stability will have profound impact on advancing our understanding in selenium regulation of optimal health. V C 2015 IUBMB Life, 68(1): [5][6][7][8][9][10][11][12] 2016

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Section: Nuclear Selenoproteins and Functionssupporting

confidence: 90%

Section: Nuclear Selenoproteins and Functionsmentioning

confidence: 99%

Nuclear selenoproteins and genome maintenance

Zhang

Zhu

et al. 2015

IUBMB Life

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“…This may explain why current models of dietary Se or selenoprotein deficiency in mice do not recapitulate normal aging sufficiently or comprehensively. Although Gpx1 −/− mice do not show aging phenotypes up to 20 months of age (Ho et al ., ), primary Gpx1 −/− embryonic fibroblasts (de Haan et al ., ) and selenoprotein H knockdown MRC‐5 cells (Wu et al ., ) show senescence‐like features in a ROS‐dependent manner. Furthermore, heterozygous mutations in SECISBP2 , a gene encoding SBP2 essential for the expression of all selenoproteins, lead to shortened telomeres in humans (Schoenmakers et al ., ), and such effect appears to be independent of telomerase (Squires et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice

Cao

Mattson

et al. 2016

Aging Cell

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SummarySelenium (Se) is a trace metalloid essential for life, but its nutritional and physiological roles during the aging process remain elusive. While telomere attrition contributes to replicative senescence mainly through persistent DNA damage response, such an aging process is mitigated in mice with inherently long telomeres. Here, weanling third generation telomerase RNA component knockout mice carrying short telomeres were fed a Se‐deficient basal diet or the diet supplemented with 0.15 ppm Se as sodium selenate to be nutritionally sufficient throughout their life. Dietary Se deprivation delayed wound healing and accelerated incidence of osteoporosis, gray hair, alopecia, and cataract, but surprisingly promoted longevity. Plasma microRNA profiling revealed a circulating signature of Se deprivation, and subsequent ontological analyses predicted dominant changes in metabolism. Consistent with this observation, dietary Se deprivation accelerated age‐dependent declines in glucose tolerance, insulin sensitivity, and glucose‐stimulated insulin production in the mice. Moreover, DNA damage and senescence responses were enhanced and Pdx1 and MafA mRNA expression were reduced in pancreas of the Se‐deficient mice. Altogether, these results suggest a novel model of aging with conceptual advances, whereby Se at low levels may be considered a hormetic chemical and decouple healthspan and longevity.

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“…Conversely, knockdown of SEPH expression renders cancer cells susceptible to H 2 O 2 (32). Recent work by Wu et al (47) showed that SEPH knockdown causes oxidative stress, which inhibits proliferation and induces senescence in fibroblasts. In that study, the authors found that H 2 O 2 exposure in SEPH-deficient cells provoked a sustained DNA damage response and senescence, which was inhibited by loss of ATM or p53 function.…”

Section: Discussionmentioning

confidence: 99%

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Cox

Tsomides

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.

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Selenoprotein H Suppresses Cellular Senescence through Genome Maintenance and Redox Regulation

Cited by 42 publications

References 79 publications

Nuclear selenoproteins and genome maintenance

Nuclear selenoproteins and genome maintenance

Opposing impacts on healthspan and longevity by limiting dietary selenium in telomere dysfunctional mice

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

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