Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span

Garschall, Kathrin; Dellago, Hanna; Gáliková, Martina; Schosserer, Markus; Flatt, Thomas; Grillari, Johannes

doi:10.1038/s41514-017-0005-z

Cited by 23 publications

(15 citation statements)

References 47 publications

(72 reference statements)

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“…Our group could demonstrate that ectopic overexpression of SNEV Prp19/Pso4 extends the replicative life span of human endothelial cells ( 102 , 103 ), as well as the organismal life span of fruit flies ( 104 ). Although SNEV Prp19/Pso4 participates also in pre-mRNA splicing ( 105 ) and in the ubiquitin/proteasome-pathway ( 106 ), we believe that its involvement in DNA damage repair is responsible for the increased stress resistance and fitness.…”

Section: Upcoming Innovative Therapeutic Approachesmentioning

confidence: 94%

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

2017

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Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development. In current cancer therapy, cellular senescence is, on the one hand, intended to occur in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, organismic aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by de- or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors. These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. We are presenting an overview of well-documented stress situations and signals, which induce senescence. Among them, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology are critically reviewed with respect to new suggestions for cancer therapy leveraging genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.

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Section: Upcoming Innovative Therapeutic Approachesmentioning

confidence: 94%

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

2017

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“…Overexpression of this gene extends replicative lifespan of endothelial cells, organismal lifespan of fruit flies and improves stress resistance at both cellular and organismal level [48,49]. Knockdown of SNEV hPRP19/hPso4 impairs adipogenesis of hASCs, as well as in Caenorhabditis elegans [50].…”

Section: Impact Of Age-induced Macromolecular Damage On (Pre-)adipocymentioning

confidence: 99%

Age-Induced Changes in White, Brite, and Brown Adipose Depots: A Mini-Review

Schosserer

Grillari²,

Wolfrum

et al. 2017

Gerontology

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Aging is a time-related process of functional decline at organelle, cellular, tissue, and organismal level that ultimately limits life. Cellular senescence is a state of permanent growth arrest in response to stress and one of the major drivers of aging and age-related disorders. Senescent cells accumulate with age, and removal of these cells delays age-related disorders in different tissues and prolongs healthy lifespan. One of the most studied aging mechanisms is the accumulation of reactive oxygen species damage in cells, organs, and organisms over time. Elevated oxidative stress is also found in metabolic diseases such as obesity, metabolic syndrome and associated disorders. Moreover, dysregulation of the energy homeostasis is also associated with aging, and many age-related genes also control energy metabolism, with the adipose organ, comprising white, brite, and brown adipocytes, as an important metabolic player in the regulation of whole-body energy homeostasis. This review summarizes transformations in the adipose organ upon aging and cellular senescence and sheds light on the reallocation of fat mass between adipose depots, on the metabolism of white and brown adipose tissue, on the regenerative potential and adipogenic differentiation capacity of preadipocytes, and on alterations in mitochondria and bioenergetics. In conclusion, the aging process is a lifelong, creeping process with gradual decline in (pre-)adipocyte function over time. Thus, slowing down the accumulation of (pre-)adipocyte damage and dysfunction, removal of senescent preadipocytes as well as blocking deleterious compounds of the senescent secretome are protective measures to maintain a lasting state of health at old age.

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“…Deletion of Prpf19 has been shown to be embryonic lethal in mice (Fortschegger et al, 2007). In human cells and Drosophila, overexpression of Prpf19 has been shown to extend lifespan by involvement of Prpf19 in DNA damage (Voglauer et al, 2006; Garschall et al, 2017). Therefore, downregulation of Prfp19 might be one of the factors contributing to embryonic lethality in double mutant mice although further experimental studies would be needed to confirm this observation.…”

Section: Discussionmentioning

confidence: 99%

High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype

Sucularli

Thomas

Koçak

et al. 2018

Gene

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In mammalian cells TPP1, encoded by the Acd gene, is a key component of the shelterin complex, which is required for telomere length maintenance and telomere protection. In mice, a hypomorphic mutation in Acd causes the adrenocortical dysplasia (acd) phenotype, which includes limb and body axis anomalies, and perinatal lethality. p53 deficiency partially rescues limb and body axis anomalies in acd mutant embryos, but not perinatal lethality, implicating p53-independent mechanisms in the acd phenotype. Loss of function of most shelterin proteins results in early embryonic lethality. Thus, study of the hypomorphic acd allele provides a unique opportunity to understand telomere dysfunction at an organismal level. The aim of this study was to identify transcriptome alterations in acd mutant and acd, p53 double mutant embryos to understand the p53-dependent and -independent factors that contribute to the mutant phenotypes in the context of the whole organism. Genes involved in developmental processes, cell cycle, metabolic pathways, tight junctions, axon guidance and signaling pathways were regulated by p53-driven mechanisms in acd mutant embryos, while genes functioning in immune response, and RNA processing were altered independently of p53 in acd, p53 double mutant embryos. To our best of knowledge, this is the first study revealing detailed transcriptomic alterations, reflecting novel p53-dependent and -independent pathways contributing to the acd phenotype. Our data confirm the importance of cell cycle and DNA repair pathways, and suggest novel links between telomere dysfunction and immune system regulation and the splicing machinery. Given the broad applicability of telomere maintenance in growth, development, and genome stability, our data will also provide a rich resource for others studying telomere maintenance and DNA damage responses in mammalian model systems.

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Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span

Cited by 23 publications

References 47 publications

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy

Age-Induced Changes in White, Brite, and Brown Adipose Depots: A Mini-Review

High-throughput gene expression analysis identifies p53-dependent and -independent pathways contributing to the adrenocortical dysplasia (acd) phenotype

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