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Article ; Online: The p53 DNA damage response and Fanconi anemia DNA repair pathway protect against acetaldehyde-induced replication stress in esophageal keratinocytes.

Peake, Jasmine D / Horne, Kalisse I / Noguchi, Chiaki / Gilligan, John P / Noguchi, Eishi

2023 Volume 22, Issue 18, Page(s) 2088–2096

Abstract: Alcohol contributes to cellular accumulation of acetaldehyde, a primary metabolite of alcohol and a major human carcinogen. Acetaldehyde can form DNA adducts and induce interstrand crosslinks (ICLs) that are repaired by the Fanconi anemia DNA repair ... ...

Abstract	Alcohol contributes to cellular accumulation of acetaldehyde, a primary metabolite of alcohol and a major human carcinogen. Acetaldehyde can form DNA adducts and induce interstrand crosslinks (ICLs) that are repaired by the Fanconi anemia DNA repair pathway (FA pathway). Individuals with deficiency in acetaldehyde detoxification or in the FA pathway have an increased risk of squamous-cell carcinomas (SCCs) including those of the esophagus. In a recent report, we described the molecular basis of acetaldehyde-induced DNA damage in esophageal keratinocytes [1]. We demonstrated that, at physiologically relevant concentrations, acetaldehyde induces DNA damage at the DNA replication fork. This resulted in replication stress, leading to activation of the ATR-Chk1-dependent cell cycle checkpoints. We also reported that the p53 DNA damage response is elevated in response to acetaldehyde and that the FA pathway limits acetaldehyde-induced genomic instability. Here, we highlight these findings and present additional results to discuss the role of the FA pathway and p53 DNA damage response in the protection against genomic instability and esophageal carcinogenesis.
MeSH term(s)	Humans ; Acetaldehyde/toxicity ; Acetaldehyde/metabolism ; Tumor Suppressor Protein p53/metabolism ; Fanconi Anemia/genetics ; Fanconi Anemia/metabolism ; DNA Damage ; Ethanol ; Genomic Instability ; DNA Repair ; Esophagus/metabolism ; Keratinocytes/metabolism ; DNA Replication
Chemical Substances	Acetaldehyde (GO1N1ZPR3B) ; Tumor Suppressor Protein p53 ; Ethanol (3K9958V90M)
Language	English
Publishing date	2023-11-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2023.2261740
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Article ; Online: Maf1 limits RNA polymerase III-directed transcription to preserve genomic integrity and extend lifespan.

Noguchi, Chiaki / Wang, Lucy / Shetty, Mihir / Mell, Joshua Chang / Sell, Christian / Noguchi, Eishi

Cell cycle (Georgetown, Tex.)

2021 Volume 20, Issue 3, Page(s) 247–255

Abstract: A key to longevity assurance is the nutrient-sensing mTOR pathway. Inhibition of mTOR extends lifespan in a variety of organisms. However, the downstream effectors of the mTOR pathway for lifespan regulation are elusive. In a recent report, we described ... ...

Abstract	A key to longevity assurance is the nutrient-sensing mTOR pathway. Inhibition of mTOR extends lifespan in a variety of organisms. However, the downstream effectors of the mTOR pathway for lifespan regulation are elusive. In a recent report, we described the role of Maf1 as a critical lifespan regulator downstream of the mTOR pathway in fission yeast. Maf1 is the master negative regulator of RNA polymerase III-directed transcription (e.g. tRNAs and 5S rRNAs) and is regulated by mTOR-mediated phosphorylation. We demonstrated that Maf1 is required for lifespan extension under calorie restriction or when mTOR is inhibited. We also showed that Maf1 prevents DNA damage at tRNA genes, which appears to contribute to lifespan maintenance by Maf1. Here we highlight these observations and present additional results to discuss the role of the mTOR-Maf1-Pol III axis in promoting genomic integrity in the face of DNA replication-transcription conflicts in order to maintain normal lifespan.
MeSH term(s)	Caloric Restriction/methods ; DNA Damage/physiology ; Longevity/physiology ; RNA Polymerase III/genetics ; RNA Polymerase III/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Schizosaccharomyces ; Schizosaccharomyces pombe Proteins/genetics ; Schizosaccharomyces pombe Proteins/metabolism ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; Transcription, Genetic/physiology
Chemical Substances	Maf1 protein, S pombe ; Repressor Proteins ; Schizosaccharomyces pombe Proteins ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; RNA Polymerase III (EC 2.7.7.6)
Language	English
Publishing date	2021-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2021.1874697
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Article: Genetic investigation of formaldehyde-induced DNA damage response in Schizosaccharomyces pombe

Anandarajan, Vinesh / Noguchi, Chiaki / Oleksak, Julia / Grothusen, Grant / Terlecky, Daniel / Noguchi, Eishi

Current genetics. 2020 June, v. 66, no. 3

2020

Abstract: Formaldehyde is a common environmental pollutant and is associated with adverse health effects. Formaldehyde is also considered to be a carcinogen because it can form DNA adducts, leading to genomic instability. How these adducts are prevented and ... ...

Abstract	Formaldehyde is a common environmental pollutant and is associated with adverse health effects. Formaldehyde is also considered to be a carcinogen because it can form DNA adducts, leading to genomic instability. How these adducts are prevented and removed is not fully understood. In this study, we used the fission yeast Schizosaccharomyces pombe as a model organism to investigate cellular tolerance pathways against formaldehyde exposure. We show that Fmd1 is a major formaldehyde dehydrogenase that functions to detoxify formaldehyde and that Fmd1 is critical to minimize formaldehyde-mediated DNA lesions. Our investigation revealed that nucleotide excision repair and homologous recombination have major roles in cellular tolerance to formaldehyde, while mutations in the Fanconi anemia, translesion synthesis, and base excision repair pathways also render cells sensitive to formaldehyde. We also demonstrate that loss of Wss1 or Wss2, proteases involved in the removal of DNA–protein crosslinks, sensitizes cells to formaldehyde and leads to replication defects. These results suggest that formaldehyde generates a variety of DNA lesions, including interstrand crosslinks, DNA–protein crosslinks, and base adducts. Thus, our genetic studies provide a framework for future investigation regarding health effects resulting from formaldehyde exposure.
Keywords	DNA adducts ; DNA damage ; DNA repair ; Fanconi anemia ; Schizosaccharomyces pombe ; carcinogens ; crosslinking ; formaldehyde ; genetic instability ; homologous recombination ; oxidoreductases ; pollutants ; proteinases
Language	English
Dates of publication	2020-06
Size	p. 593-605.
Publishing place	Springer Berlin Heidelberg
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	282876-5
ISSN	1432-0983 ; 0172-8083
ISSN (online)	1432-0983
ISSN	0172-8083
DOI	10.1007/s00294-020-01057-z
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Article ; Online: Genetic investigation of formaldehyde-induced DNA damage response in Schizosaccharomyces pombe.

Anandarajan, Vinesh / Noguchi, Chiaki / Oleksak, Julia / Grothusen, Grant / Terlecky, Daniel / Noguchi, Eishi

Current genetics

2020 Volume 66, Issue 3, Page(s) 593–605

Abstract	Formaldehyde is a common environmental pollutant and is associated with adverse health effects. Formaldehyde is also considered to be a carcinogen because it can form DNA adducts, leading to genomic instability. How these adducts are prevented and removed is not fully understood. In this study, we used the fission yeast Schizosaccharomyces pombe as a model organism to investigate cellular tolerance pathways against formaldehyde exposure. We show that Fmd1 is a major formaldehyde dehydrogenase that functions to detoxify formaldehyde and that Fmd1 is critical to minimize formaldehyde-mediated DNA lesions. Our investigation revealed that nucleotide excision repair and homologous recombination have major roles in cellular tolerance to formaldehyde, while mutations in the Fanconi anemia, translesion synthesis, and base excision repair pathways also render cells sensitive to formaldehyde. We also demonstrate that loss of Wss1 or Wss2, proteases involved in the removal of DNA-protein crosslinks, sensitizes cells to formaldehyde and leads to replication defects. These results suggest that formaldehyde generates a variety of DNA lesions, including interstrand crosslinks, DNA-protein crosslinks, and base adducts. Thus, our genetic studies provide a framework for future investigation regarding health effects resulting from formaldehyde exposure.
MeSH term(s)	DNA Damage ; DNA Repair ; DNA Replication ; Fanconi Anemia Complementation Group Proteins/genetics ; Fanconi Anemia Complementation Group Proteins/metabolism ; Formaldehyde/adverse effects ; Formaldehyde/toxicity ; Homologous Recombination ; Respiratory Hypersensitivity ; Schizosaccharomyces/drug effects ; Schizosaccharomyces/genetics ; Schizosaccharomyces/metabolism
Chemical Substances	Fanconi Anemia Complementation Group Proteins ; Formaldehyde (1HG84L3525)
Language	English
Publishing date	2020-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	282876-5
ISSN	1432-0983 ; 0172-8083
ISSN (online)	1432-0983
ISSN	0172-8083
DOI	10.1007/s00294-020-01057-z
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Article ; Online: FANCD2 limits acetaldehyde-induced genomic instability during DNA replication in esophageal keratinocytes.

Peake, Jasmine D / Noguchi, Chiaki / Lin, Baicheng / Theriault, Amber / O'Connor, Margaret / Sheth, Shivani / Tanaka, Koji / Nakagawa, Hiroshi / Noguchi, Eishi

Molecular oncology

2021 Volume 15, Issue 11, Page(s) 3109–3124

Abstract: Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young-onset head and neck squamous cell carcinomas (SCCs) and esophageal SCC. The FA DNA repair pathway is activated upon DNA damage induced by ... ...

Abstract	Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young-onset head and neck squamous cell carcinomas (SCCs) and esophageal SCC. The FA DNA repair pathway is activated upon DNA damage induced by acetaldehyde, a chief alcohol metabolite and one of the major carcinogens in humans. However, the molecular basis of acetaldehyde-induced genomic instability in SCCs of the head and neck and of the esophagus in FA remains elusive. Here, we report the effects of acetaldehyde on replication stress response in esophageal epithelial cells (keratinocytes). Acetaldehyde-exposed esophageal keratinocytes displayed accumulation of DNA damage foci consisting of 53BP1 and BRCA1. At physiologically relevant concentrations, acetaldehyde activated the ATR-Chk1 pathway, leading to S- and G2/M-phase delay with accumulation of the FA complementation group D2 protein (FANCD2) at the sites of DNA synthesis, suggesting that acetaldehyde impedes replication fork progression. Consistently, depletion of the replication fork protection protein Timeless led to elevated DNA damage upon acetaldehyde exposure. Furthermore, FANCD2 depletion exacerbated replication abnormalities, elevated DNA damage, and led to apoptotic cell death, indicating that FANCD2 prevents acetaldehyde-induced genomic instability in esophageal keratinocytes. These observations contribute to our understanding of the mechanisms that drive genomic instability in FA patients and alcohol-related carcinogenesis, thereby providing a translational implication in the development of more effective therapies for SCCs.
MeSH term(s)	Acetaldehyde/metabolism ; Acetaldehyde/toxicity ; DNA Damage ; DNA Repair/genetics ; DNA Replication/genetics ; Esophagus/pathology ; Fanconi Anemia/genetics ; Fanconi Anemia/metabolism ; Fanconi Anemia/pathology ; Fanconi Anemia Complementation Group D2 Protein/genetics ; Fanconi Anemia Complementation Group D2 Protein/metabolism ; Genomic Instability ; Humans ; Keratinocytes/metabolism
Chemical Substances	FANCD2 protein, human ; Fanconi Anemia Complementation Group D2 Protein ; Acetaldehyde (GO1N1ZPR3B)
Language	English
Publishing date	2021-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13072
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Article ; Online: Efficacy and safety of ivermectin in patients with mild COVID-19 in Japan and Thailand.

Mikamo, Hiroshige / Takahashi, Satoshi / Yamagishi, Yuka / Hirakawa, Akihiro / Harada, Toshiyuki / Nagashima, Hirotaka / Noguchi, Chiaki / Masuko, Kentaro / Maekawa, Hiromitsu / Kashii, Tatsuhiko / Ohbayashi, Hiroyuki / Hosokawa, Shinichiro / Maejima, Katsuyuki / Yamato, Masaya / Manosuthi, Weerawat / Paiboonpol, Supachai / Suganami, Hideki / Tanigawa, Ryohei / Kawamura, Hitoshi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy

2023 Volume 30, Issue 6, Page(s) 536–543

Abstract: Background: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and ...

Abstract	Background: Ivermectin is an antiparasitic drug administered to hundreds of millions of people worldwide. Fundamental research suggests that ivermectin is effective against coronavirus disease 2019 (COVID-19); therefore, we investigated the efficacy and safety of ivermectin as a COVID-19 treatment option. Methods: This multi-regional (Japan and Thailand), multicenter, placebo-controlled, randomized, double-blind, parallel-group, Phase III study evaluated the efficacy and safety of ivermectin in patients with mild COVID-19 (IVERMILCO Study). The participants took a specified number of the investigational product (ivermectin or placebo) tablets of, adjusted to a dose of 0.3-0.4 mg/kg, orally on an empty stomach once daily for three days. The primary efficacy endpoint was the time at which clinical symptoms first showed an improving trend by 168 h after investigational product administration. Results: A total of 1030 eligible participants were assigned to receive the investigational product; 502 participants received ivermectin and 527 participants received a placebo. The primary efficacy endpoint was approximately 96 h (approximately four days) for both ivermectin and placebo groups, which did not show statistically significant difference (stratified log-rank test, p = 0.61). The incidence of adverse events and adverse drug reactions did not show statistically significant differences between the ivermectin and placebo groups (chi-square test, p = 0.97, p = 0.59). Conclusions: The results show that ivermectin (0.3-0.4 mg/kg), as a treatment for patients with mild COVID-19, is ineffective; however, its safety has been confirmed for participants, including minor participants of 12 years or older (IVERMILCO Study ClinicalTrials.gov number, NCT05056883.).
MeSH term(s)	Humans ; COVID-19/epidemiology ; Ivermectin/adverse effects ; SARS-CoV-2 ; COVID-19 Drug Treatment ; Japan/epidemiology ; Thailand/epidemiology ; Double-Blind Method ; Treatment Outcome
Chemical Substances	Ivermectin (70288-86-7)
Language	English
Publishing date	2023-12-27
Publishing country	Netherlands
Document type	Randomized Controlled Trial ; Multicenter Study ; Clinical Trial, Phase III ; Journal Article
ZDB-ID	1355399-9
ISSN	1437-7780 ; 1341-321X
ISSN (online)	1437-7780
ISSN	1341-321X
DOI	10.1016/j.jiac.2023.12.012
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Article ; Online: Proteasome-dependent degradation of replisome components regulates faithful DNA replication.

Roseaulin, Laura C / Noguchi, Chiaki / Noguchi, Eishi

Cell cycle (Georgetown, Tex.)

2013 Volume 12, Issue 16, Page(s) 2564–2569

Abstract: The replication machinery, or the replisome, collides with a variety of obstacles during the normal process of DNA replication. In addition to damaged template DNA, numerous chromosome regions are considered to be difficult to replicate owing to the ... ...

Abstract	The replication machinery, or the replisome, collides with a variety of obstacles during the normal process of DNA replication. In addition to damaged template DNA, numerous chromosome regions are considered to be difficult to replicate owing to the presence of DNA secondary structures and DNA-binding proteins. Under these conditions, the replication fork stalls, generating replication stress. Stalled forks are prone to collapse, posing serious threats to genomic integrity. It is generally thought that the replication checkpoint functions to stabilize the replisome and replication fork structure upon replication stress. This is important in order to allow DNA replication to resume once the problem is solved. However, our recent studies demonstrated that some replisome components undergo proteasome-dependent degradation during DNA replication in the fission yeast Schizosaccharomyces pombe. Our investigation has revealed the involvement of the SCF(Pof3) (Skp1-Cullin/Cdc53-F-box) ubiquitin ligase in replisome regulation. We also demonstrated that forced accumulation of the replisome components leads to abnormal DNA replication upon replication stress. Here we review these findings and present additional data indicating the importance of replisome degradation for DNA replication. Our studies suggest that cells activate an alternative pathway to degrade replisome components in order to preserve genomic integrity.
MeSH term(s)	DNA Helicases/metabolism ; DNA Replication/physiology ; Models, Genetic ; Phosphatidylinositol 3-Kinases/metabolism ; Proteasome Endopeptidase Complex/physiology ; SKP Cullin F-Box Protein Ligases/metabolism ; Schizosaccharomyces
Chemical Substances	SKP Cullin F-Box Protein Ligases (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2013-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.25692
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Article ; Online: The NuA4 acetyltransferase and histone H4 acetylation promote replication recovery after topoisomerase I-poisoning.

Noguchi, Chiaki / Singh, Tanu / Ziegler, Melissa A / Peake, Jasmine D / Khair, Lyne / Aza, Ana / Nakamura, Toru M / Noguchi, Eishi

Epigenetics & chromatin

2019 Volume 12, Issue 1, Page(s) 24

Abstract: Background: Histone acetylation plays an important role in DNA replication and repair because replicating chromatin is subject to dynamic changes in its structures. However, its precise mechanism remains elusive. In this report, we describe roles of the ...

Abstract	Background: Histone acetylation plays an important role in DNA replication and repair because replicating chromatin is subject to dynamic changes in its structures. However, its precise mechanism remains elusive. In this report, we describe roles of the NuA4 acetyltransferase and histone H4 acetylation in replication fork protection in the fission yeast Schizosaccharomyces pombe. Results: Downregulation of NuA4 subunits renders cells highly sensitive to camptothecin, a compound that induces replication fork breakage. Defects in NuA4 function or mutations in histone H4 acetylation sites lead to impaired recovery of collapsed replication forks and elevated levels of Rad52 DNA repair foci, indicating the role of histone H4 acetylation in DNA replication and fork repair. We also show that Vid21 interacts with the Swi1-Swi3 replication fork protection complex and that Swi1 stabilizes Vid21 and promotes efficient histone H4 acetylation. Furthermore, our genetic analysis demonstrates that loss of Swi1 further sensitizes NuA4 and histone H4 mutant cells to replication fork breakage. Conclusion: Considering that Swi1 plays a critical role in replication fork protection, our results indicate that NuA4 and histone H4 acetylation promote repair of broken DNA replication forks.
MeSH term(s)	Acetylation ; Camptothecin/toxicity ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; DNA Replication ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Histone Acetyltransferases/genetics ; Histone Acetyltransferases/metabolism ; Histones/genetics ; Histones/metabolism ; Schizosaccharomyces/genetics ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/genetics ; Schizosaccharomyces pombe Proteins/metabolism ; Topoisomerase I Inhibitors/toxicity
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Histones ; Schizosaccharomyces pombe Proteins ; Topoisomerase I Inhibitors ; rad52 protein, S pombe ; swi1 protein, S pombe ; Histone Acetyltransferases (EC 2.3.1.48) ; Camptothecin (XT3Z54Z28A)
Language	English
Publishing date	2019-04-16
Publishing country	England
Document type	Journal Article ; Research Support, American Recovery and Reinvestment Act ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2462129-8
ISSN	1756-8935 ; 1756-8935
ISSN (online)	1756-8935
ISSN	1756-8935
DOI	10.1186/s13072-019-0271-z
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Article ; Online: Maf1-dependent transcriptional regulation of tRNAs prevents genomic instability and is associated with extended lifespan.

Shetty, Mihir / Noguchi, Chiaki / Wilson, Sydney / Martinez, Esteban / Shiozaki, Kazuhiro / Sell, Christian / Mell, Joshua Chang / Noguchi, Eishi

Aging cell

2019 Volume 19, Issue 2, Page(s) e13068

Abstract: Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in ... ...

Abstract	Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1's function in tRNA repression is inhibited by mTOR-dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1∆ cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1∆ cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1∆ cells. Interestingly, maf1∆ cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1∆ cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1∆ cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1∆ cells. We propose that Maf1-dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes.
MeSH term(s)	Chromatin Immunoprecipitation ; DNA Damage/genetics ; Gene Expression Regulation, Fungal ; Genomic Instability/genetics ; Glucose/metabolism ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Protein Biosynthesis/genetics ; Protein Biosynthesis/physiology ; Protein Phosphatase 2/genetics ; Protein Phosphatase 2/metabolism ; RNA, Transfer/biosynthesis ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; Rad52 DNA Repair and Recombination Protein/genetics ; Rad52 DNA Repair and Recombination Protein/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; Schizosaccharomyces/genetics ; Schizosaccharomyces/metabolism ; Schizosaccharomyces/physiology ; Schizosaccharomyces pombe Proteins/genetics ; Schizosaccharomyces pombe Proteins/metabolism
Chemical Substances	Maf1 protein, S pombe ; Rad52 DNA Repair and Recombination Protein ; Repressor Proteins ; Schizosaccharomyces pombe Proteins ; RNA, Transfer (9014-25-9) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Protein Phosphatase 2 (EC 3.1.3.16) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2019-12-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/acel.13068
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Article: Sap1 promotes the association of the replication fork protection complex with chromatin and is involved in the replication checkpoint in Schizosaccharomyces pombe.

Noguchi, Chiaki / Noguchi, Eishi

Genetics

2007 Volume 175, Issue 2, Page(s) 553–566

Abstract: Sap1 is involved in replication fork pausing at rDNA repeats and functions during mating-type switching in Schizosaccharomyces pombe. These two roles are dependent on the ability of Sap1 to bind specific DNA sequences at the rDNA and mating-type loci, ... ...

Abstract	Sap1 is involved in replication fork pausing at rDNA repeats and functions during mating-type switching in Schizosaccharomyces pombe. These two roles are dependent on the ability of Sap1 to bind specific DNA sequences at the rDNA and mating-type loci, respectively. In S. pombe, Swi1 and Swi3 form the replication fork protection complex (FPC) and play important roles in the activation of the replication checkpoint and the stabilization of stalled replication forks. Here we describe the roles of Sap1 in the replication checkpoint. We show that Sap1 is involved in the activation of the replication checkpoint kinase Cds1 and that sap1 mutant cells accumulate spontaneous DNA damage during the S- and G2-phases, which is indicative of fork damage. We also show that sap1 mutants have a defect in the resumption of DNA replication after fork arrest. Sap1 is localized at the replication origin ori2004 and this localization is required for the association of the FPC with chromatin. We propose that Sap1 is required to recruit the FPC to chromatin, thereby contributing to the activation of the replication checkpoint and the stabilization of replication forks.
MeSH term(s)	Chromatin/metabolism ; DNA Damage ; DNA Repair ; DNA Replication ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/isolation & purification ; DNA-Binding Proteins/metabolism ; Gene Dosage ; Mutant Proteins/isolation & purification ; Mutant Proteins/metabolism ; Mutation/genetics ; Replication Origin ; S Phase ; Schizosaccharomyces/cytology ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/genetics ; Schizosaccharomyces pombe Proteins/isolation & purification ; Schizosaccharomyces pombe Proteins/metabolism ; Suppression, Genetic
Chemical Substances	Chromatin ; DNA-Binding Proteins ; Mutant Proteins ; Sap1 protein, S pombe ; Schizosaccharomyces pombe Proteins ; Swi3 protein, S pombe ; rad52 protein, S pombe
Language	English
Publishing date	2007-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2167-2
ISSN	1943-2631 ; 0016-6731
ISSN (online)	1943-2631
ISSN	0016-6731
DOI	10.1534/genetics.106.065334
Database	MEDical Literature Analysis and Retrieval System OnLINE

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