Редактирование: PARP1

Poly [ADP-ribose] polymerase 1 (EC 2.4.2.30) (PARP-1) (ADP-ribosyltransferase diphtheria toxin-like 1) (ARTD1) (DNA ADP-ribosyltransferase PARP1) (EC 2.4.2.-) (NAD( ) ADP-ribosyltransferase 1) (ADPRT 1) (Poly[ADP-ribose] synthase 1) (Protein poly-ADP-ribosyltransferase PARP1) (EC 2.4.2.-) [ADPRT] [PPOL]

==Publications==

{{medline-entry
|title=Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109421
|abstract=Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near [[SENP7]], [[MOB1B]], [[CARMIL1]], [[PRRC2A]], [[TERF2]], and [[RFWD3]], and our results support recently identified [[PARP1]], [[POT1]], [[ATM]], and [[MPHOSPH6]] loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
|mesh-terms=* Genome-Wide Association Study
* Humans
* Leukocytes
* Nucleotides
* Telomere
|keywords=* Mendelian randomisation
* age-related disease
* biological aging
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826
}}
{{medline-entry
|title=Metabolism and biochemical properties of nicotinamide adenine dinucleotide (NAD) analogs, nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31511627
|abstract=Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that regulates various metabolic pathways, including glycolysis, β-oxidation, and oxidative phosphorylation. Additionally, NAD serves as a substrate for poly(ADP-ribose) polymerase (PARP), sirtuin, and NAD glycohydrolase, and it regulates DNA repair, gene expression, energy metabolism, and stress responses. Many studies have demonstrated that NAD metabolism is deeply involved in aging and aging-related diseases. Previously, we demonstrated that nicotinamide guanine dinucleotide (NGD) and nicotinamide hypoxanthine dinucleotide (NHD), which are analogs of NAD, are significantly increased in Nmnat3-overexpressing mice. However, there is insufficient knowledge about NGD and NHD in vivo. In the present study, we aimed to investigate the metabolism and biochemical properties of these NAD analogs. We demonstrated that endogenous NGD and NHD were found in various murine tissues, and their synthesis and degradation partially rely on Nmnat3 and [[CD38]]. We have also shown that NGD and NHD serve as coenzymes for alcohol dehydrogenase (ADH) in vitro, although their affinity is much lower than that of NAD. On the other hand, NGD and NHD cannot be used as substrates for [[SIRT1]], [[SIRT3]], and [[PARP1]]. These results reveal the basic metabolism of NGD and NHD and also highlight their biological function as coenzymes.
|mesh-terms=* Aging
* Animals
* Guanine Nucleotides
* Guanosine Triphosphate
* Inosine Triphosphate
* Mice
* NAD
* Poly(ADP-ribose) Polymerases
* Sirtuins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739475
}}
{{medline-entry
|title=Topological DNA damage, telomere attrition and T cell senescence during chronic viral infections.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31285747
|abstract=T cells play a key role in controlling viral infections; however, the underlying mechanisms regulating their functions during human viral infections remain incompletely understood. Here, we used [[CD4]] T cells derived from individuals with chronic viral infections or healthy T cells treated with camptothecin (CPT) - a topoisomerase I (Top 1) inhibitor - as a model to investigate the role of DNA topology in reprogramming telomeric DNA damage responses (DDR) and remodeling T cell functions. We demonstrated that Top 1 protein expression and enzyme activity were significantly inhibited, while the Top 1 cleavage complex (TOP1cc) was trapped in genomic DNA, in T cells derived from individuals with chronic viral (HCV, HBV, or HIV) infections. Top 1 inhibition by CPT treatment of healthy [[CD4]] T cells caused topological DNA damage, telomere attrition, and T cell apoptosis or dysfunction via inducing Top1cc accumulation, [[PARP1]] cleavage, and failure in DNA repair, thus recapitulating T cell dysregulation in the setting of chronic viral infections. Moreover, T cells from virally infected subjects with inhibited Top 1 activity were more vulnerable to CPT-induced topological DNA damage and cell apoptosis, indicating an important role for Top 1 in securing DNA integrity and cell survival. These findings provide novel insights into the molecular mechanisms for immunomodulation by chronic viral infections via disrupting DNA topology to induce telomeric DNA damage, T cell senescence, apoptosis and dysfunction. As such, restoring the impaired DNA topologic machinery may offer a new strategy for maintaining T cell function against human viral diseases.

|keywords=* HBV
* HCV
* HIV
* T cell senescence
* Telomere attrition
* Topological DNA damage
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591813
}}
{{medline-entry
|title=[[PARP1]] inhibitor (PJ34) improves the function of aging-induced endothelial progenitor cells by preserving intracellular NAD  levels and increasing [[SIRT1]] activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30139380
|abstract=Nicotinamide adenine dinucleotide (NAD ) is a critical molecule involved in various biological functions. Poly (ADP-ribose) polymerase 1 ([[PARP1]]) and sirtuin 1 ([[SIRT1]]) affect cellular NAD  levels and play essential roles in regulating metabolism. However, there has been little research on the effects of [[PARP1]] and [[SIRT1]] crosstalk during senescence. We isolated endothelial progenitor cells (EPCs) from human umbilical cord blood and treated them with a [[PARP1]] inhibitor (PJ34). Using a stress-induced premature aging model built by H O , transfection with adenoviral vectors, and Western blot analysis, we observed that PJ34 treatment preserved intracellular NAD  levels, increased [[SIRT1]] activity, decreased p53 acetylation, and improved the function of stress-induced premature aging EPCs. Our results suggest that PJ34 improves the function of aging-induced EPCs and may contribute to cellular therapies for atherosclerosis.
|mesh-terms=* Cell Movement
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Endothelial Progenitor Cells
* Fetal Blood
* Gene Expression Regulation
* Humans
* Hydrogen Peroxide
* NAD
* Oxidative Stress
* Phenanthrenes
* Poly (ADP-Ribose) Polymerase-1
* Primary Cell Culture
* Signal Transduction
* Sirtuin 1
* Tumor Suppressor Protein p53
|keywords=* Endothelial progenitor cells
* Nicotinamide adenine dinucleotide
* Poly (ADP-ribose) polymerase 1
* Senescence
* Sirtuin 1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107962
}}
{{medline-entry
|title=Maternal high calorie diet induces mitochondrial dysfunction and senescence phenotype in subcutaneous fat of newborn mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29137352
|abstract=Mitochondrial dysfunction, inflammation and senescence-like features are observed in adipose depots in aging and obesity. Herein, we evaluated how maternal high calorie diet (HCD) may impact on subcutaneous adipose tissue (sAT) of the newborn mice. Adult C57BL/6J mice were randomly divided in three groups: normal calorie diet (NCD), HCD and HCD supplemented with niacin 8 weeks before mating. Mothers and pups were then sacrificed and metabolic and molecular analyses were carried out on sAT. HCD induced mitochondria dysfunction in mothers without inflammation and senescence, whereas in pups we also revealed the occurrence of senescent phenotype. The mitochondrial dysfunction-associated senescence in pups was accompanied by a drop in NAD /NADH ratio and alteration in the NAD -dependent enzymes [[PARP1]] and [[SIRT1]]. Importantly, maternal dietary supplementation with niacin during gestation and lactation restrained NAD /NADH decrease imposed by HCD limiting inflammatory cytokine production and senescence phenotype in newborn sAT. Given the fundamental role of sAT in buffering nutrient overload and avoiding pathogenic ectopic fat accumulation, we suggest that NAD  boosting strategies during maternal HCD could be helpful in limiting sAT dysfunction in newborn.

|keywords=* Gerotarget
* NAD
* adipocytes
* aging
* inflammation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663524
}}
{{medline-entry
|title=Acute telomerase components depletion triggers oxidative stress as an early event previous to telomeric shortening.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29055871
|abstract=Loss of function of dyskerin ([[DKC1]]), [[NOP10]] and TIN2 are responsible for different inheritance patterns of Dyskeratosis congenita (DC; ORPHA1775). They are key components of telomerase ([[DKC1]] and [[NOP10]]) and shelterin (TIN2), and play an important role in telomere homeostasis. They participate in several fundamental cellular processes by contributing to Dyskeratosis congenita through mechanisms that are not fully understood. Presence of oxidative stress was postulated to result from telomerase ablation. However, the resulting disturbed redox status can promote telomere attrition by generating a vicious circle, which promotes cellular senescence. This fact prompted us to study if acute loss of [[DKC1]], [[NOP10]] and [[TINF2]] can promote redox disequilibrium as an early event when telomere shortening has not yet taken place. We generated siRNA-mediated ([[DKC1]], [[NOP10]] and [[TINF2]]) cell lines by RNA interference, which was confirmed by mRNA and protein expression analyses. No telomere shortening occurred in any silenced cell line. Depletion of H/ACA ribonucleoproteins [[DKC1]] and [[NOP10]] diminished telomerase activity via TERC down-regulation, and produced alterations in pseudouridylation and ribosomal biogenesis. An increase in the GSSG/GSH ratio, carbonylated proteins and oxidized peroxiredoxin-6 was observed, in addition to MnSOD and TRX1 overexpression in the siRNA DC cells. Likewise, high PARylation levels and high [[PARP1]] protein expression were detected. In contrast, the silenced [[TINF2]] cells did not alter any evaluated oxidative stress marker. Altogether these findings lead us to conclude that loss of [[DKC1]] and [[NOP10]] functions induces oxidative stress in a telomere shortening independent manner.
|mesh-terms=* Cell Cycle Proteins
* Cellular Senescence
* DNA Damage
* Dyskeratosis Congenita
* HeLa Cells
* Humans
* Nuclear Proteins
* Oxidative Stress
* RNA Interference
* Ribonucleoproteins, Small Nucleolar
* Telomerase
* Telomere Shortening
* Telomere-Binding Proteins
|keywords=* Aging
* Antioxidant
* DNA damage
* Oxidative stress
* Telomeropathies
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650655
}}
{{medline-entry
|title=Molecular evolutionary patterns of NAD /Sirtuin aging signaling pathway across taxa.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28767699
|abstract=A deeper understanding of the conserved molecular mechanisms in different taxa have been made possible only because of the evolutionary conservation of crucial signaling pathways. In the present study, we explored the molecular evolutionary pattern of selection signatures in 51 species for 10 genes which are important components of NAD /Sirtuin pathway and have already been directly linked to lifespan extension in worms and mice. Selection pressure analysis using PAML program revealed that [[MRPS5]] and [[PPARGC1A]] were under significant constraints because of their functional significance. FOXO3a also displayed strong purifying selection. All three sirtuins, which were [[SIRT1]], [[SIRT2]] and [[SIRT6]], displayed a great degree of conservation between taxa, which is consistent with the previous report. A significant evolutionary constraint is seen on the anti-oxidant gene, [[SOD3]]. As expected, [[TP53]] gene was under significant selection pressure in mammals, owing to its major role in tumor progression. Poly-ADP-ribose polymerase (PARP) genes displayed the most sites under positive selection. Further 3D structural analysis of [[PARP1]] and [[PARP2]] protein revealed that some of these positively selected sites caused a change in the electrostatic potential of the protein structure, which may allow a change in its interaction with other proteins and molecules ultimately leading to difference in the function. Although the functional significance of the positively selected sites could not be established in the variants databases, yet it will be interesting to see if these sites actually affect the function of [[PARP1]] and [[PARP2]].
|mesh-terms=* Aging
* Animals
* Evolution, Molecular
* Helminths
* Humans
* Mice
* NAD
* Poly (ADP-Ribose) Polymerase-1
* Poly(ADP-ribose) Polymerases
* Selection, Genetic
* Signal Transduction
* Sirtuins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540417
}}
{{medline-entry
|title=The NAD /[[PARP1]]/[[SIRT1]] Axis in Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28537485
|abstract=NAD  levels decline with age in diverse animals from Caenorhabditis elegans to mice. Raising NAD  levels by dietary supplementation with NAD  precursors, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), improves mitochondrial function and muscle and neural and melanocyte stem cell function in mice, as well as increases murine life span. Decreased NAD  levels with age reduce [[SIRT1]] function and reduce the mitochondrial unfolded protein response, which can be overcome by NR supplementation. Decreased NAD  levels cause NAD -binding protein DBC1 to form a complex with [[PARP1]], inhibiting poly(adenosine diphosphate-ribose) polymerase (PARP) catalytic activity. Old mice have increased amounts of DBC1-[[PARP1]] complexes, lower PARP activity, increased DNA damage, and reduced nonhomologous end joining and homologous recombination repair. DBC1-[[PARP1]] complexes in old mice can be broken by increasing NAD  levels through treatment with NMN, reducing DNA damage and restoring PARP activity to youthful levels. The mechanism of declining NAD  levels and its fundamental importance to aging are yet to be elucidated. There is a correlation of PARP activity with mammalian life span that suggests that NAD /[[SIRT1]]/[[PARP1]] may be more significant than the modest effects on life span observed for NR supplementation in old mice. The NAD /[[PARP1]]/[[SIRT1]] axis may link NAD  levels and DNA damage with the apparent epigenomic DNA methylation clocks that have been described.
|mesh-terms=* Aging
* Animals
* DNA Damage
* Humans
* Mice
* NAD
* Poly(ADP-ribose) Polymerases
* Signal Transduction
* Sirtuin 1
|keywords=* DBC1/CCAR2
* NAD 
* PARP1
* SIRT1
* epigenome
|full-text-url=https://sci-hub.do/10.1089/rej.2017.1980
}}
{{medline-entry
|title=A conserved NAD  binding pocket that regulates protein-protein interactions during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28336669
|abstract=DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD  (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD  to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting [[PARP1]] [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein. As mice age and NAD  concentrations decline, DBC1 is increasingly bound to [[PARP1]], causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD  Thus, NAD  directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Conserved Sequence
* DNA Damage
* DNA Repair
* Fibroblasts
* HEK293 Cells
* Humans
* Mice
* Models, Molecular
* NAD
* Neoplasms
* Paraquat
* Poly (ADP-Ribose) Polymerase-1
* Protein Interaction Domains and Motifs
* RNA, Small Interfering
* Radiation Tolerance
* Sequence Homology, Nucleic Acid

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456119
}}
{{medline-entry
|title=Melatonin regulates [[PARP1]] to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28247536
|abstract=Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS. Here, we report two different but potentially coherent epigenetic strategies for melatonin regulation of SASP. The interaction between the telomeric repeat-containing RNA (TERRA) and PARP-1 stimulates the SASP, which was attenuated by 67.9% (illustrated by the case of IL8) by treatment with melatonin. Through binding to macroH2A1.1, PARP-1 recruits CREB-binding protein (CBP) to mediate acetylation of H2BK120, which positively regulates the expression of target SASP genes, and this process is interrupted by melatonin. Consequently, the findings provide novel insight into melatonin's epigenetic role via modulating PARP-1 in suppression of SASP gene expression in OIS-induced senescent cells. Our studies identify melatonin as a novel anti-SASP molecule, define PARP-1 as a new target by which melatonin regulates SASP, and establish a new epigenetic paradigm for a pharmacological mechanism by which melatonin interrupts PARP-1 interaction with the telomeric long noncoding RNA(lncRNA) or chromatin.
|mesh-terms=* Cell Line
* Cells, Cultured
* Cellular Senescence
* Fibroblasts
* Humans
* Lung
* Melatonin
* Poly (ADP-Ribose) Polymerase-1
|keywords=* 
SASP

* 
TERRA

* PARP1
* cellular senescence
* histone acetylation
* melatonin
|full-text-url=https://sci-hub.do/10.1111/jpi.12405
}}
{{medline-entry
|title=The Ubiquitin-like with PHD and Ring Finger Domains 1 ([[UHRF1]])/DNA Methyltransferase 1 ([[DNMT1]]) Axis Is a Primary Regulator of Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28100769
|abstract=As senescence develops, cells sequentially acquire diverse senescent phenotypes along with simultaneous multistage gene reprogramming. It remains unclear what acts as the key regulator of the collective changes in gene expression at initiation of senescent reprogramming. Here we analyzed time series gene expression profiles obtained in two different senescence models in human diploid fibroblasts: replicative senescence and H O -induced senescence. Our results demonstrate that suppression of DNA methyltransferase 1 ([[DNMT1]])-mediated DNA methylation activity was an initial event prior to the display of senescent phenotypes. We identified seven [[DNMT1]]-interacting proteins, ubiquitin-like with PHD and ring finger domains 1 ([[UHRF1]]), [[EZH2]], [[CHEK1]], [[SUV39H1]], [[CBX5]], [[PARP1]], and [[HELLS]] (also known as LSH (lymphoid-specific helicase) 1), as being commonly down-regulated at the same time point as [[DNMT1]] in both senescence models. Knockdown experiments revealed that, among the [[DNMT1]]-interacting proteins, only [[UHRF1]] knockdown suppressed [[DNMT1]] transcription. However, [[UHRF1]] overexpression alone did not induce [[DNMT1]] expression, indicating that [[UHRF1]] was essential but not sufficient for [[DNMT1]] transcription. Although [[UHRF1]] knockdown effectively induced senescence, this was significantly attenuated by [[DNMT1]] overexpression, clearly implicating the [[UHRF1]]/[[DNMT1]] axis in senescence. Bioinformatics analysis further identified [[WNT5A]] as a downstream effector of [[UHRF1]]/[[DNMT1]]-mediated senescence. Senescence-associated hypomethylation was found at base pairs -1569 to -1363 from the transcription start site of the [[WNT5A]] gene in senescent human diploid fibroblasts. As expected, [[WNT5A]] overexpression induced senescent phenotypes. Overall, our results indicate that decreased [[UHRF1]] expression is a key initial event in the suppression of [[DNMT1]]-mediated DNA methylation and in the consequent induction of senescence via increasing [[WNT5A]] expression.
|mesh-terms=* CCAAT-Enhancer-Binding Proteins
* Cellular Senescence
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Fibroblasts
* Gene Expression Profiling
* Gene Expression Regulation
* HEK293 Cells
* Histones
* Humans
* Hydrogen Peroxide
* Male
* Oligonucleotide Array Sequence Analysis
* Phenotype
* Promoter Regions, Genetic
* Protein Binding
* Protein Domains
* RNA, Small Interfering
* Ubiquitin-Protein Ligases
* Wnt-5a Protein
* beta-Galactosidase
|keywords=* DNA methylation
* cellular senescence
* gene expression
* gene regulation
* microarray
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339756
}}
{{medline-entry
|title=A serum miRNA profile of human longevity: findings from the Baltimore Longitudinal Study of Aging (BLSA).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27824314
|abstract=In [i]C. elegans[/i], miRNAs are genetic biomarkers of aging. Similarly, multiple miRNAs are differentially expressed between younger and older persons, suggesting that miRNA-regulated biological mechanisms affecting aging are evolutionarily conserved. Previous human studies have not considered participants' lifespans, a key factor in identifying biomarkers of aging. Using PCR arrays, we measured miRNA levels from serum samples obtained longitudinally at ages 50, 55, and 60 from 16 non-Hispanic males who had documented lifespans from 58 to 92. Numerous miRNAs showed significant changes in expression levels. At age 50, 24 miRNAs were significantly upregulated, and 73 were significantly downregulated in the long-lived subgroup (76-92 years) as compared with the short-lived subgroup (58-75 years). In long-lived participants, the most upregulated was miR-373-5p, while the most downregulated was miR-15b-5p. Longitudinally, significant Pearson correlations were observed between lifespan and expression of nine miRNAs (p value<0.05). Six of these nine miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, 1225-3p) were also significantly up- or downregulated when comparing long-lived and short-lived participants. Twenty-four validated targets of these miRNAs encoded aging-associated proteins, including [[PARP1]], [[IGF1R]], and [[IGF2R]]. We propose that the expression profiles of the six miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, and 1225-3p) may be useful biomarkers of aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Animals
* Biomarkers
* Caenorhabditis elegans
* Down-Regulation
* Gene Expression Profiling
* Humans
* Longevity
* Longitudinal Studies
* Male
* MicroRNAs
* Middle Aged
* Pilot Projects
* Polymerase Chain Reaction
* Up-Regulation
|keywords=* aging
* biomarker
* long-lived
* longitudinal study
* miRNA
* short-lived
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5191881
}}
{{medline-entry
|title=Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27791127
|abstract=Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 ([[PARP1]]). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates [[PARP1]] and leads to accelerated aging in Caenorhabditis elegans In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.
|mesh-terms=* Cell Line, Tumor
* Cockayne Syndrome
* DNA Damage
* DNA Helicases
* DNA Repair
* DNA Repair Enzymes
* DNA, Neoplasm
* DNA, Ribosomal
* G-Quadruplexes
* Gene Knockdown Techniques
* Humans
* Neuroblastoma
* Poly (ADP-Ribose) Polymerase-1
* Poly-ADP-Ribose Binding Proteins
* Transcription Factors
* Transcription, Genetic
|keywords=* CSA
* CSB
* Cockayne syndrome
* aging
* nucleolus
* polymerase I transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098674
}}
{{medline-entry
|title=Sperm-associated antigen 9 ([[SPAG9]]) promotes the survival and tumor growth of triple-negative breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27449044
|abstract=Recently, we demonstrated the association of sperm-associated antigen 9 ([[SPAG9]]) expression with breast cancer. Among breast cancer, 15 % of the cancers are diagnosed as triple-negative breast cancers (TNBC) based on hormone receptor status and represent an important clinical challenge because of lack of effective available targeted therapy. Therefore, in the present investigation, plasmid-based small hairpin (small hairpin RNA (shRNA)) approach was used to ablate [[SPAG9]] in aggressive breast cancer cell line model (MDA-[[MB]]-231) in order to understand the role of [[SPAG9]] at molecular level in apoptosis, cell cycle, and epithelial-to-mesenchymal transition (EMT) signaling. Our data in MDA-[[MB]]-231 cells showed that ablation of [[SPAG9]] resulted in membrane blebbing, increased mitochondrial membrane potential, DNA fragmentation, phosphatidyl serine surface expression, and caspase activation. [[SPAG9]] depletion also resulted in cell cycle arrest in G0-G1 phase and induced cellular senescence. In addition, in in vitro and in vivo xenograft studies, ablation of [[SPAG9]] resulted in upregulation of p21 along with pro-apoptotic molecules such as BAK, [[BAX]], BIM, [[BID]], NOXA, AIF, Cyto-C, [[PARP1]], [[APAF1]], Caspase 3, and Caspase 9 and epithelial marker, E-cadherin. Also, [[SPAG9]]-depleted cells showed downregulation of cyclin B1, cyclin D1, cyclin E, [[CDK1]], [[CDK4]], [[CDK6]], [[BCL2]], Bcl-xL, [[XIAP]], cIAP2, [[MCL1]], GRP78, SLUG, SNAIL, TWIST, vimentin, N-cadherin, [[MMP2]], [[MMP3]], [[MMP9]], SMA, and β-catenin. Collectively, our data suggests that [[SPAG9]] promotes tumor growth by inhibiting apoptosis, altering cell cycle, and enhancing EMT signaling in in vitro cells and in vivo mouse model. Hence, [[SPAG9]] may be a potential novel target for therapeutic use in TNBC treatment.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Animals
* Apoptosis
* Blotting, Western
* Cell Proliferation
* Fluorescent Antibody Technique, Indirect
* Humans
* Immunoenzyme Techniques
* Membrane Potential, Mitochondrial
* Mice
* RNA, Small Interfering
* Triple Negative Breast Neoplasms
* Tumor Cells, Cultured
|keywords=* Apoptosis
* Cell growth
* Cellular motility
* SPAG9
* Senescence
* Triple-negative breast cancer
* Tumor growth
|full-text-url=https://sci-hub.do/10.1007/s13277-016-5240-6
}}
{{medline-entry
|title=Differential cytotoxicity induced by the Titanium(IV)Salan complex Tc52 in G2-phase independent of DNA damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27412346
|abstract=Chemotherapy is one of the major treatment modalities for cancer. Metal-based compounds such as derivatives of cisplatin are in the front line of therapy against a subset of cancers, but their use is restricted by severe side-effects and the induction of resistance in treated tumors. Subsequent research focused on development of cytotoxic metal-complexes without cross-resistance to cisplatin and reduced side-effects. This led to the discovery of first-generation titanium(IV)salan complexes, which reached clinical trials but lacked efficacy. New-generation titanium (IV)salan-complexes show promising anti-tumor activity in mice, but their molecular mechanism of cytotoxicity is completely unknown. Four different human cell lines were analyzed in their responses to a toxic (Tc52) and a structurally highly related but non-toxic (Tc53) titanium(IV)salan complex. Viability assays were used to reveal a suitable treatment range, flow-cytometry analysis was performed to monitor the impact of dosage and treatment time on cell-cycle distribution and cell death. Potential DNA strand break induction and crosslinking was investigated by immunostaining of damage markers as well as automated fluorometric analysis of DNA unwinding. Changes in nuclear morphology were analyzed by DAPI staining. Acidic beta-galactosidase activity together with morphological changes was monitored to detect cellular senescence. Western blotting was used to analyze induction of pro-apoptotic markers such as activated caspase7 and cleavage of [[PARP1]], and general stress kinase p38. Here we show that the titanium(IV)salan Tc52 is effective in inducing cell death in the lower micromolar range. Surprisingly, Tc52 does not target DNA contrary to expectations deduced from the reported activity of other titanium complexes. Instead, Tc52 application interferes with progression from G2-phase into mitosis and induces apoptotic cell death in tested tumor cells. Contrarily, human fibroblasts undergo senescence in a time and dose-dependent manner. As deduced from fluorescence studies, the potential cellular target seems to be the cytoskeleton. In summary, we could demonstrate in four different human cell lines that tumor cells were specifically killed without induction of major cytotoxicity in non-tumorigenic cells. Absence of DNA damaging activity and the cell-cycle block in G2 instead of mitosis makes Tc52 an attractive compound for further investigations in cancer treatment.
|mesh-terms=* Antineoplastic Agents
* Apoptosis
* Blotting, Western
* Caspase 7
* Cell Division
* Cell Line, Tumor
* Cell Nucleus
* Cell Survival
* Cellular Senescence
* Coordination Complexes
* Cytoskeleton
* DNA Damage
* Flow Cytometry
* G2 Phase
* HEK293 Cells
* HeLa Cells
* Humans
* Poly (ADP-Ribose) Polymerase-1
* Radioisotopes
* Titanium
* p38 Mitogen-Activated Protein Kinases
|keywords=* Apoptosis
* Cell-cycle
* Senescence
* Titanium(IV)salan complex
* Tumorigenicity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944496
}}
{{medline-entry
|title=All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26359359
|abstract=Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a [[LMNA]] mutation which produces progerin, a mutant lamin A precursor. Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. Since the [[LMNA]] promoter contains a retinoic acid responsive element, we investigated if all-trans retinoic acid administration could lower progerin levels in cultured fibroblasts. We also evaluated the effect of associating rapamycin, which induces autophagic degradation of progerin and prelamin A. We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. These effects rescue cell dynamics and cellular proliferation through recovery of DNA damage response factor [[PARP1]] and chromatin-associated nuclear envelope proteins LAP2α and BAF. The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders. 
|mesh-terms=* Antineoplastic Agents
* Blotting, Western
* Cell Cycle
* Cell Proliferation
* Cells, Cultured
* DNA-Binding Proteins
* Drug Synergism
* Fibroblasts
* Gene Expression
* Histones
* Humans
* Lamin Type A
* Lysine
* Membrane Proteins
* Methylation
* Microscopy, Electron, Transmission
* Microscopy, Fluorescence
* Nuclear Proteins
* Phenotype
* Poly (ADP-Ribose) Polymerase-1
* Poly(ADP-ribose) Polymerases
* Progeria
* Reverse Transcriptase Polymerase Chain Reaction
* Sirolimus
* Tretinoin
|keywords=* DNA damage and repair
* Hutchinson Gilford progeria syndrome
* all-trans retinoic acid
* premature aging
* rapamycin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745772
}}
{{medline-entry
|title=SIRT6 rescues the age related decline in base excision repair in a [[PARP1]]-dependent manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25607651
|abstract=In principle, a decline in base excision repair (BER) efficiency with age should lead to genomic instability and ultimately contribute to the onset of the aging phenotype. Although multiple studies have indicated a negative link between aging and BER, the change of BER efficiency with age in humans has not been systematically analyzed. Here, with foreskin fibroblasts isolated from 19 donors between 20 and 64 y of age, we report a significant decline of BER efficiency with age using a newly developed GFP reactivation assay. We further observed a very strong negative correlation between age and the expression levels of SIRT6, a factor which is known to maintain genomic integrity by improving DNA double strand break (DSB) repair. Our mechanistic study suggests that, similar to the regulatory role that SIRT6 plays in DNA DSB repair, SIRT6 regulates BER in a [[PARP1]]-depdendent manner. Moreover, overexpression of SIRT6 rescues the decline of BER in aged fibroblasts. In summary, our results uncovered the regulatory mechanisms of BER by SIRT6, suggesting that SIRT6 reactivation in aging tissues may help delay the process of aging through improving BER. 
|mesh-terms=* Adult
* Aging
* Cells, Cultured
* DNA Breaks, Double-Stranded
* DNA Repair
* Fibroblasts
* Foreskin
* Genomic Instability
* Humans
* Light
* Male
* Middle Aged
* Phenanthrenes
* Poly(ADP-ribose) Polymerase Inhibitors
* Poly(ADP-ribose) Polymerases
* RNA Interference
* RNA, Small Interfering
* Sirtuins
|keywords=* PARP1
* SIRT6
* SIRTUIN
* aging
* base excision repair
* mono-ADP-ribosylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614943
}}
{{medline-entry
|title=RecQ helicases and [[PARP1]] team up in maintaining genome integrity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25555679
|abstract=Genome instability represents a primary hallmark of aging and cancer. RecQL helicases (i.e., RECQL1, WRN, BLM, RECQL4, RECQL5) as well as poly(ADP-ribose) polymerases (PARPs, in particular [[PARP1]]) represent two central quality control systems to preserve genome integrity in mammalian cells. Consistently, both enzymatic families have been linked to mechanisms of aging and carcinogenesis in mice and humans. This is in accordance with clinical and epidemiological findings demonstrating that defects in three RecQL helicases, i.e., WRN, BLM, RECQL4, are related to human progeroid and cancer predisposition syndromes, i.e., Werner, Bloom, and Rothmund Thomson syndrome, respectively. Moreover, [[PARP1]] hypomorphy is associated with a higher risk for certain types of cancer. On a molecular level, RecQL helicases and [[PARP1]] are involved in the control of DNA repair, telomere maintenance, and replicative stress. Notably, over the last decade, it became apparent that all five RecQL helicases physically or functionally interact with [[PARP1]] and/or its enzymatic product poly(ADP-ribose) (PAR). Furthermore, a profound body of evidence revealed that the cooperative function of RECQLs and [[PARP1]] represents an important factor for maintaining genome integrity. In this review, we summarize the status quo of this molecular cooperation and discuss open questions that provide a basis for future studies to dissect the cooperative functions of RecQL helicases and [[PARP1]] in aging and carcinogenesis. 
|mesh-terms=* Aging
* Animals
* DNA
* Genome, Human
* Genomic Instability
* Humans
* Mice
* Poly (ADP-Ribose) Polymerase-1
* Poly(ADP-ribose) Polymerases
* RecQ Helicases
|keywords=* Aging
* BLM
* Cancer
* Poly(ADP-ribose) polymerase
* RECQL
* WRN
|full-text-url=https://sci-hub.do/10.1016/j.arr.2014.12.006
}}
{{medline-entry
|title=Mechanisms controlling the smooth muscle cell death in progeria via down-regulation of poly(ADP-ribose) polymerase 1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24843141
|abstract=Hutchinson-Gilford progeria syndrome (HGPS) is a severe human premature aging disorder caused by a lamin A mutant named progerin. Death occurs at a mean age of 13 y from cardiovascular problems. Previous studies revealed loss of vascular smooth muscle cells (SMCs) in the media of large arteries in a patient with HGPS and two mouse models, suggesting a causal connection between the SMC loss and cardiovascular malfunction. However, the mechanisms of how progerin leads to massive SMC loss are unknown. In this study, using SMCs differentiated from HGPS induced pluripotent stem cells, we show that HGPS SMCs exhibit a profound proliferative defect, which is primarily caused by caspase-independent cell death. Importantly, progerin accumulation stimulates a powerful suppression of [[PARP1]] and consequently triggers an activation of the error-prone nonhomologous end joining response. As a result, most HGPS SMCs exhibit prolonged mitosis and die of mitotic catastrophe. This study demonstrates a critical role of [[PARP1]] in mediating SMC loss in patients with HGPS and elucidates a molecular pathway underlying the progressive SMC loss in progeria. 
|mesh-terms=* Aging
* Cell Death
* Cell Differentiation
* Cell Survival
* Down-Regulation
* Fibroblasts
* G2 Phase
* Humans
* Myocytes, Smooth Muscle
* Pluripotent Stem Cells
* Poly (ADP-Ribose) Polymerase-1
* Poly(ADP-ribose) Polymerases
* Primary Cell Culture
* Progeria
* S Phase
* Skin

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050581
}}
{{medline-entry
|title=Redox regulation of [[SIRT1]] in inflammation and cellular senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23542362
|abstract=Sirtuin 1 ([[SIRT1]]) regulates inflammation, aging (life span and health span), calorie restriction/energetics, mitochondrial biogenesis, stress resistance, cellular senescence, endothelial functions, apoptosis/autophagy, and circadian rhythms through deacetylation of transcription factors and histones. [[SIRT1]] level and activity are decreased in chronic inflammatory conditions and aging, in which oxidative stress occurs. [[SIRT1]] is regulated by a NAD( )-dependent DNA repair enzyme, poly(ADP-ribose) polymerase-1 ([[PARP1]]), and subsequent NAD( ) depletion by oxidative stress may have consequent effects on inflammatory and stress responses as well as cellular senescence. [[SIRT1]] has been shown to undergo covalent oxidative modifications by cigarette smoke-derived oxidants/aldehydes, leading to posttranslational modifications, inactivation, and protein degradation. Furthermore, oxidant/carbonyl stress-mediated reduction of [[SIRT1]] leads to the loss of its control on acetylation of target proteins including p53, RelA/p65, and [[FOXO3]], thereby enhancing the inflammatory, prosenescent, and apoptotic responses, as well as endothelial dysfunction. In this review, the mechanisms of cigarette smoke/oxidant-mediated redox posttranslational modifications of [[SIRT1]] and its roles in [[PARP1]] and NF-κB activation, and [[FOXO3]] and eNOS regulation, as well as chromatin remodeling/histone modifications during inflammaging, are discussed. Furthermore, we have also discussed various novel ways to activate [[SIRT1]] either directly or indirectly, which may have therapeutic potential in attenuating inflammation and premature senescence involved in chronic lung diseases. 
|mesh-terms=* Active Transport, Cell Nucleus
* Animals
* Cellular Senescence
* Forkhead Box Protein O3
* Forkhead Transcription Factors
* Histones
* Humans
* Inflammation
* NF-kappa B
* Nitric Oxide Synthase Type III
* Oxidation-Reduction
* Oxidative Stress
* Poly (ADP-Ribose) Polymerase-1
* Poly(ADP-ribose) Polymerases
* Signal Transduction
* Sirtuin 1
* Transcription Factor RelA
|keywords=* COPD
* FOXO3
* Free radicals
* GSH
* Inflammation
* NF-κB
* Oxidants
* Redox signaling
* SIRT1
* Senescence
* Tobacco smoke
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3762912
}}