scholarly journals MUT-7 Provides Molecular Insight into the Werner Syndrome Exonuclease

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3457
Author(s):  
Tsung-Yuan Hsu ◽  
Ling-Nung Hsu ◽  
Shih-Yu Chen ◽  
Bi-Tzen Juang
Keyword(s):  
Genetic Disease ◽  
Werner Syndrome ◽  
Accelerated Aging ◽  
Feedback Regulation ◽  
Premature Aging ◽  
Negative Feedback Regulation ◽  
Physiological Conditions ◽  
C Elegans ◽  
Interfering Rna ◽  
Insight Into

Werner syndrome (WS) is a rare recessive genetic disease characterized by premature aging. Individuals with this disorder develop normally during childhood, but their physiological conditions exacerbate the aging process in late adolescence. WS is caused by mutation of the human WS gene (WRN), which encodes two main domains, a 3′-5′ exonuclease and a 3′-5′ helicase. Caenorhabditis elegans expresses human WRN orthologs as two different proteins: MUT-7, which has a 3′-5′ exonuclease domain, and C. elegans WRN-1 (CeWRN-1), which has only helicase domains. These unique proteins dynamically regulate olfactory memory in C. elegans, providing insight into the molecular roles of WRN domains in humans. In this review, we specifically focus on characterizing the function of MUT-7 in small interfering RNA (siRNA) synthesis in the cytoplasm and the roles of siRNA in directing nuclear CeWRN-1 loading onto a heterochromatin complex to induce negative feedback regulation. Further studies on the different contributions of the 3′-5′ exonuclease and helicase domains in the molecular mechanism will provide clues to the accelerated aging processes in WS.

A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence

2021 ◽  
Vol 13 (575) ◽  
pp. eabd2655
Author(s):  
Wei Wang ◽  
Yuxuan Zheng ◽  
Shuhui Sun ◽  
Wei Li ◽  
Moshi Song ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Werner Syndrome ◽  
Embryonic Stem ◽  
Accelerated Aging ◽  
Premature Aging ◽  
Mesenchymal Precursor Cells ◽  
Genome Wide ◽  
A Genome ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Understanding the genetic and epigenetic bases of cellular senescence is instrumental in developing interventions to slow aging. We performed genome-wide CRISPR-Cas9–based screens using two types of human mesenchymal precursor cells (hMPCs) exhibiting accelerated senescence. The hMPCs were derived from human embryonic stem cells carrying the pathogenic mutations that cause the accelerated aging diseases Werner syndrome and Hutchinson-Gilford progeria syndrome. Genes whose deficiency alleviated cellular senescence were identified, including KAT7, a histone acetyltransferase, which ranked as a top hit in both progeroid hMPC models. Inactivation of KAT7 decreased histone H3 lysine 14 acetylation, repressed p15INK4b transcription, and alleviated hMPC senescence. Moreover, lentiviral vectors encoding Cas9/sg-Kat7, given intravenously, alleviated hepatocyte senescence and liver aging and extended life span in physiologically aged mice as well as progeroid Zmpste24−/− mice that exhibit a premature aging phenotype. CRISPR-Cas9–based genetic screening is a robust method for systematically uncovering senescence genes such as KAT7, which may represent a therapeutic target for developing aging interventions.

scholarly journals Dynamical modelling of haematopoiesis: an integrated view over the system in homeostasis and under perturbation

2013 ◽  
Vol 10 (80) ◽  
pp. 20120817 ◽  
Author(s):  
Erica Manesso ◽  
José Teles ◽  
David Bryder ◽  
Carsten Peterson
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Blood Cells ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Adult Mice ◽  
Potential Applications ◽  
Population Sizes ◽  
Haematopoietic System ◽  
Insight Into

A very high number of different types of blood cells must be generated daily through a process called haematopoiesis in order to meet the physiological requirements of the organism. All blood cells originate from a population of relatively few haematopoietic stem cells residing in the bone marrow, which give rise to specific progenitors through different lineages. Steady-state dynamics are governed by cell division and commitment rates as well as by population sizes, while feedback components guarantee the restoration of steady-state conditions. In this study, all parameters governing these processes were estimated in a computational model to describe the haematopoietic hierarchy in adult mice. The model consisted of ordinary differential equations and included negative feedback regulation. A combination of literature data, a novel divide et impera approach for steady-state calculations and stochastic optimization allowed one to reduce possible configurations of the system. The model was able to recapitulate the fundamental steady-state features of haematopoiesis and simulate the re-establishment of steady-state conditions after haemorrhage and bone marrow transplantation. This computational approach to the haematopoietic system is novel and provides insight into the dynamics and the nature of possible solutions, with potential applications in both fundamental and clinical research.

scholarly journals Evolution of the RECQ Family of Helicases: A Drosophila Homolog, Dmblm, Is Similar to the Human Bloom Syndrome Gene

Genetics ◽  
1999 ◽  
Vol 151 (3) ◽  
pp. 1027-1039
Author(s):  
Kohji Kusano ◽  
Mark E Berres ◽  
William R Engels
Keyword(s):  
Drosophila Melanogaster ◽  
Homo Sapiens ◽  
Werner Syndrome ◽  
Bloom Syndrome ◽  
Dna Helicase ◽  
Functional Similarity ◽  
Premature Aging ◽  
Model Systems ◽  
C Elegans ◽  
Blm Gene

Abstract Several eukaryotic homologs of the Escherichia coli RecQ DNA helicase have been found. These include the human BLM gene, whose mutation results in Bloom syndrome, and the human WRN gene, whose mutation leads to Werner syndrome resembling premature aging. We cloned a Drosophila melanogaster homolog of the RECQ helicase family, Dmblm (Drosophila melanogaster Bloom), which encodes a putative 1487-amino-acid protein. Phylogenetic and dot plot analyses for the RECQ family, including 10 eukaryotic and 3 prokaryotic genes, indicate Dmblm is most closely related to the Homo sapiens BLM gene, suggesting functional similarity. Also, we found that Dmblm cDNA partially rescued the sensitivity to methyl methanesulfonate of Saccharomyces cerevisiae sgs1 mutant, demonstrating the presence of a functional similarity between Dmblm and SGS1. Our analyses identify four possible subfamilies in the RECQ family: (1) the BLM subgroup (H. sapiens Bloom, D. melanogaster Dmblm, and Caenorhabditis elegans T04A11.6); (2) the yeast RECQ subgroup (S. cerevisiae SGS1 and Schizosaccharomyces pombe rqh1/rad12); (3) the RECQL/Q1 subgroup (H. sapiens RECQL/Q1 and C. elegans K02F3.1); and (4) the WRN subgroup (H. sapiens Werner and C. elegans F18C5.2). This result may indicate that metazoans hold at least three RECQ genes, each of which may have a different function, and that multiple RECQ genes diverged with the generation of multicellular organisms. We propose that invertebrates such as nematodes and insects are useful as model systems of human genetic diseases.

scholarly journals Hereditary syndromes with signs of premature aging

2020 ◽  
Vol 22 (3) ◽  
pp. 4-18
Author(s):  
Olga O. Golounina ◽  
Valentin V. Fadeev ◽  
Zhanna E. Belaya
Keyword(s):  
Molecular Mechanisms ◽  
Werner Syndrome ◽  
Accelerated Aging ◽  
Scientific Data ◽  
The Body ◽  
Premature Aging ◽  
Hereditary Diseases ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Age Related Changes

Aging is a multi-factor biological process that inevitably affects everyone. Degenerative processes, starting at the cellular and molecular levels, gradually influence the change in the functional capabilities of all organs and systems. Progeroid syndromes (from Greek. progērōs prematurely old), or premature aging syndromes, represent clinically and genetically heterogeneous group of rare hereditary diseases characterized by accelerated aging of the body. Progeria and segmental progeroid syndromes include more than a dozen diseases, but the most clear signs of premature aging are evident in Hutchinson-Guilford Progeria Syndrome and Werner Syndrome. This review summarizes the latest scientific data reflecting the etiology and clinical picture of progeria and segmental progeroid syndromes in humans. Molecular mechanisms of aging are considered, using the example of progeroid syndromes. Modern possibilities and potential ways of influencing the mechanisms of the development of age-related changes are discussed. Further study of genetic causes, as well as the development of treatment for progeria and segmental progeroid syndromes, may be a promising direction for correcting age-related changes and increasing life expectancy.

scholarly journals Werner syndrome helicase modulates G4 DNA-dependent transcription and opposes mechanistically distinct senescence-associated gene expression programs

2015 ◽  
Author(s):  
Weiliang Tang ◽  
Ana I. Robles ◽  
Richard P. Beyer ◽  
Lucas T. Gray ◽  
Giang Hong Nguyen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genome Stability ◽  
Werner Syndrome ◽  
Premature Aging ◽  
Dna Motifs ◽  
Trna Synthetases ◽  
Over Expression ◽  
G4 Dna ◽  
G Quadruplex ◽  
Insight Into

Werner syndrome (WS) is a prototypic heritable adult human progeroid syndrome in which signs of premature aging are associated with genetic instability and an elevated risk of specific types of cancer. We have quantified mRNA and microRNA (miRNA) expression in WS patient fibroblasts, and in WRN-depleted fibroblasts. Genes down-regulated in WS patient fibroblasts were highly enriched in G-quadruplex (G4) DNA motifs. The strength, location and strand specificity of this association provide strong experimental evidence that G4 motifs or motif-dependent G-quadruplexes are bound by WRN in human cells to modulate gene expression. The expression of many miRNAs was perturbed by loss of WRN function. WRN depletion altered the expression of >500 miRNAs. miRNAs linked to cell signaling, genome stability assurance and tumorigenesis were among the small number of these miRNAs that were persistently altered in WS patient fibroblasts. An unexpected and highly distinct finding in WS cells was the coordinate over-expression of nearly all cytoplasmic tRNA synthetases and their associated AIMP proteins. Our results provide new insight into WS pathogenesis, and identify therapeutically accessible mechanisms that may drive disease pathogenesis in WS and in the general population.

scholarly journals NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Evandro F. Fang ◽  
Yujun Hou ◽  
Sofie Lautrup ◽  
Martin Borch Jensen ◽  
Beimeng Yang ◽  
...  
Keyword(s):  
Werner Syndrome ◽  
Accelerated Aging ◽  
Dna Helicase ◽  
Premature Aging ◽  
Metabolic Dysfunction ◽  
Gene Encoding ◽  
Metabolic Phenotypes ◽  
Cell Dysfunction ◽  
Underlying Mechanisms ◽  
Invertebrate Models

AbstractMetabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

scholarly journals C. elegans orthologs MUT-7/CeWRN-1 of Werner syndrome protein regulate neuronal plasticity

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tsung-Yuan Hsu ◽  
Bo Zhang ◽  
Noelle D L'Etoile ◽  
Bi-Tzen Juang
Keyword(s):  
Gene Expression ◽  
Guanylyl Cyclase ◽  
Neuronal Plasticity ◽  
Small Interfering Rna ◽  
Werner Syndrome ◽  
C Elegans ◽  
Werner Syndrome Protein ◽  
Olfactory Plasticity ◽  
Syndrome Protein ◽  
Interfering Rna

Caenorhabditis elegans expresses human Werner syndrome protein (WRN) orthologs as two distinct proteins: MUT-7, with a 3′−5′ exonuclease domain, and CeWRN-1, with helicase domains. How these domains cooperate remains unclear. Here, we demonstrate the different contributions of MUT-7 and CeWRN-1 to 22G small interfering RNA (siRNA) synthesis and the plasticity of neuronal signaling. MUT-7 acts specifically in the cytoplasm to promote siRNA biogenesis and in the nucleus to associate with CeWRN-1. The import of siRNA by the nuclear Argonaute NRDE-3 promotes the loading of the heterochromatin-binding protein HP1 homolog HPL-2 onto specific loci. This heterochromatin complex represses the gene expression of the guanylyl cyclase ODR-1 to direct olfactory plasticity in C. elegans. Our findings suggest that the exonuclease and helicase domains of human WRN may act in concert to promote RNA-dependent loading into a heterochromatin complex, and the failure of this entire process reduces plasticity in postmitotic neurons.

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