Редактирование: ATRX

Transcriptional regulator ATRX (EC 3.6.4.12) (ATP-dependent helicase ATRX) (X-linked helicase II) (X-linked nuclear protein) (XNP) (Znf-HX) [RAD54L] [XH2]

==Publications==

{{medline-entry
|title=[[ATRX]]-[[DAXX]] Complex Expression Levels and Telomere Length in Normal Young and Elder Autopsy Human Brains.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31361513
|abstract=The chromatin-remodeling complex [[ATRX]]/[[DAXX]] is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. [[ATRX]] is involved in nucleosome configuration and maintenance of higher order chromatin structure, and [[DAXX]] is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed [[ATRX]] and [[DAXX]] expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the [[ATRX]]-[[DAXX]] complex involvement in telomere maintenance and brain aging.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Adult
* Aged
* Aged, 80 and over
* Aging
* Brain
* Co-Repressor Proteins
* Humans
* Middle Aged
* Molecular Chaperones
* Nuclear Proteins
* Telomere Homeostasis
* X-linked Nuclear Protein
|keywords=* ATRX
* DAXX
* aging
* gene and protein expressions
* human brain tissues
* telomere length
|full-text-url=https://sci-hub.do/10.1089/dna.2019.4752
}}
{{medline-entry
|title=Inactivation of hepatic [[ATRX]] in [i]Atrx[/i] Foxg1cre mice prevents reversal of aging-like phenotypes by thyroxine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29883366
|abstract=[[ATRX]] is an ATP-dependent chromatin remodeler required for the maintenance of genomic integrity. We previously reported that conditional [i]Atrx[/i] ablation in the mouse embryonic forebrain and anterior pituitary using the Foxg1cre driver causes reduced health and lifespan. In these mice, premature aging-like phenotypes were accompanied by low circulating levels of insulin-like growth factor 1 (IGF-1) and thyroxine (T4), hormones that maintain stem cell pools and normal metabolic profiles, respectively. Based on emerging evidence that T4 stimulates expression of IGF-1 in pre-pubertal mice, we tested whether T4 supplementation in [i]Atrx[/i] Foxg1cre mice could restore IGF-1 levels and ameliorate premature aging-like phenotypes. Despite restoration of normal serum T4 levels, we did not observe improvements in circulating IGF-1. In the liver, thyroid hormone target genes were differentially affected upon T4 treatment, with [i]Igf1[/i] and several other thyroid hormone responsive genes failing to recover normal expression levels. These findings hinted at Cre-mediated [i]Atrx[/i] inactivation in the liver of [i]Atrx[/i] Foxg1cre mice, which we confirmed. We conclude that the phenotypes observed in the [i]Atrx[/i] Foxg1cre mice can be explained in part by a role of [[ATRX]] in the liver to promote T4-mediated [i]Igf1[/i] expression, thus explaining the inefficacy of T4 therapy observed in this study.
|mesh-terms=* Aging
* Animals
* Blood Glucose
* Forkhead Transcription Factors
* Gene Expression Regulation
* Insulin-Like Growth Factor I
* Liver
* Mice
* Mice, Transgenic
* Nerve Tissue Proteins
* Subcutaneous Fat
* Thyroxine
* X-linked Nuclear Protein
|keywords=* ATRX
* IGF-1
* premature aging
* thyroid hormone
* transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046231
}}
{{medline-entry
|title=Mechanistic understanding of the role of [[ATRX]] in senescence provides new insight for combinatorial therapies with [[CDK4]] inhibitors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29404388
|abstract=Senescence is an irreversible form of growth arrest and is generally considered a favorable outcome of cancer therapies, yet little is known about the molecular events that distinguish this state from readily reversible growth arrest (i.e. quiescence). Recently, we discovered that during therapy induced senescence the chromatin remodeling protein α-thalassemia, mental retardation, X-linked ([[ATRX]]) represses Harvey rat sarcoma viral oncogene homolog ([i]HRAS)[/i], and repression of [i]HRAS[/i] is necessary to establish senescence, suggesting how new clinical combinations might be used to achieve durable senescence.

|keywords=* ATRX
* CDK4 inhibitors
* Therapy induced senescence
* geroconversion
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791849
}}
{{medline-entry
|title=GBM-associated mutations and altered protein expression are more common in young patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27579614
|abstract=Geriatric glioblastoma (GBM) patients have a poorer prognosis than younger patients, but [[IDH1]]/2 mutations (more common in younger patients) confer a favorable prognosis. We compared key GBM molecular alterations between an elderly (age ≥ 70) and younger (18 < = age < = 45) cohort to explore potential therapeutic opportunities. Alterations more prevalent in the young GBM cohort compared to the older cohort (P < 0.05) were: overexpression of [[ALK]], [[RRM1]], [[TUBB3]] and mutation of [[ATRX]], [[BRAF]], [[IDH1]], and [[TP53]]. However, [[PTEN]] mutation was significantly more frequent in older patients. Among patients with wild-type [[IDH1]]/2 status, TOPO1 expression was higher in younger patients, whereas [[MGMT]] methylation was more frequent in older patients. Within the molecularly-defined IDH wild-type GBM cohort, younger patients had significantly more mutations in [[PDGFRA]], [[PTPN11]], [[SMARCA4]], [[BRAF]] and [[TP53]]. GBMs from 178 elderly patients and 197 young patients were analyzed using DNA sequencing, immunohistochemistry, in situ hybridization, and [[MGMT]]-methylation assay to ascertain mutational and amplification/expressional status. Significant molecular differences occurred in GBMs from elderly and young patients. Except for the older cohort's more frequent [[PTEN]] mutation and [[MGMT]] methylation, younger patients had a higher frequency of potential therapeutic targets.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aging
* Biomarkers, Tumor
* Brain Neoplasms
* Cohort Studies
* DNA Methylation
* DNA Mutational Analysis
* ErbB Receptors
* Gene Expression Regulation, Neoplastic
* Glioblastoma
* Humans
* Mutation
* Tumor Suppressor Protein p53
|keywords=* DNA sequencing
* GBM
* mutational analysis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342491
}}
{{medline-entry
|title=Postovulatory aging affects dynamics of mRNA, expression and localization of maternal effect proteins, spindle integrity and pericentromeric proteins in mouse oocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26577303
|abstract=Is the postovulatory aging-dependent differential decrease of mRNAs and polyadenylation of mRNAs coded by maternal effect genes associated with altered abundance and distribution of maternal effect and RNA-binding proteins (MSY2)? Postovulatory aging results in differential reduction in abundance of maternal effect proteins, loss of RNA-binding proteins from specific cytoplasmic domains and critical alterations of pericentromeric proteins without globally affecting protein abundance. Oocyte postovulatory aging is associated with differential alteration in polyadenylation and reduction in abundance of mRNAs coded by selected maternal effect genes. RNA-binding and -processing proteins are involved in storage, polyadenylation and degradation of mRNAs thus regulating stage-specific recruitment of maternal mRNAs, while chromosomal proteins that are stage-specifically expressed at pericentromeres, contribute to control of chromosome segregation and regulation of gene expression in the zygote. Germinal vesicle (GV) and metaphase II (MII) oocytes from sexually mature C57B1/6J female mice were investigated. Denuded in vivo or in vitro matured MII oocytes were postovulatory aged and analyzed by semiquantitative confocal microscopy for abundance and localization of polyadenylated RNAs, proteins of maternal effect genes (transcription activator BRG1 also known as ATP-dependent helicase SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) and NOD-like receptor family pyrin domain containing 5 (NLRP5) also known as MATER), RNA-binding proteins (MSY2 also known as germ cell-specific Y-box-binding protein, YBX2), and post-transcriptionally modified histones (trimethylated histone H3K9 and acetylated histone H4K12), as well as pericentromeric [[ATRX]] (alpha thalassemia/mental retardation syndrome X-linked, also termed ATP-dependent helicase [[ATRX]] or X-linked nuclear protein (XNP)). For proteome analysis five replicates of 30 mouse oocytes were analyzed by selected reaction monitoring ([[SRM]]). GV and MII oocytes were obtained from large antral follicles or ampullae of sexually mature mice, respectively. Denuded MII oocytes were aged for 24 h post ovulation. For analysis of distribution and abundance of polyadenylated RNAs fixed oocytes were in situ hybridized to Cy5 labeled oligo(dT)20 nucleotides. Absolute quantification of protein concentration per oocyte of selected proteins was done by [[SRM]] proteome analysis. Relative abundance of [[ATRX]] was assessed by confocal laser scanning microscopy (CLSM) of whole mount formaldehyde fixed oocytes or after removal of zona and spreading. MSY2 protein distribution and abundance was studied in MII oocytes prior to, during and after exposure to nocodazole, or after aging for 2 h in presence of H2O2 or for 24 h in presence of a glutathione donor, glutathione ethylester (GEE). The significant reduction in abundance of proteins (P < 0.001) translated from maternal mRNAs was independent of polyadenylation status, while their protein localization was not significantly changed by aging. Most of other proteins quantified by [[SRM]] analysis did not significantly change in abundance upon aging except MSY2 and [[GTSF1]]. MSY2 was enriched in the subcortical RNP domain (SCRD) and in the spindle chromosome complex (SCC) in a distinct pattern, right and left to the chromosomes. There was a significant loss of MSY2 from the SCRD (P < 0.001) and the spindle after postovulatory aging. Microtubule de- and repolymerization caused reversible loss of MSY2 spindle-association whereas H2O2 stress did not significantly decrease MSY2 abundance. Aging in presence of GEE decreased significantly (P < 0.05) the aging-related overall and cytoplasmic loss of MSY2. Postovulatory aging increased significantly spindle abnormalities, unaligned chromosomes, and abundance of acetylated histone H4K12, and decreased pericentromeric trimethylated histone H3K9 (all P < 0.001). Spreading revealed a highly significant increase in pericentromeric [[ATRX]] (P < 0.001) upon ageing. Thus, the significantly reduced abundance of MSY2 protein, especially at the SCRD and the spindle may disturb the spatial control and timely recruitment, deadenylation and degradation of developmentally important RNAs. An autonomous program of degradation appears to exist which transiently and specifically induces the loss and displacement of transcripts and specific maternal proteins independent of fertilization in aging oocytes and thereby can critically affect chromosome segregation and gene expression in the embryo after fertilization. We used the mouse oocyte to study processes associated with postovulatory aging, which may not entirely reflect processes in aging human oocytes. However, increases in spindle abnormalities, unaligned chromosomes and H4K12 acetylated histones, as well as in mRNA abundance and polyadenylation have been observed also in aged human oocytes suggesting conserved processes in aging. Postovulatory aging precociously induces alterations in expression and epigenetic modifications of chromatin by [[ATRX]] and in histone pattern in MII oocytes that normally occur after fertilization, possibly contributing to disturbances in the oocyte-to-embryo transition (OET) and the zygotic gene activation (ZGA). These observations in mouse oocytes are also relevant to explain disturbances and reduced developmental potential of aged human oocytes and caution to prevent oocyte aging in vivo and in vitro. The study has been supported by the German Research Foundation (DFG) (EI 199/7-1 | GR 1138/12-1 | HO 949/21-1 and FOR 1041). There is no competing interest.
|mesh-terms=* Animals
* Antigens
* Cellular Senescence
* Centromere
* Egg Proteins
* Female
* Gene Expression
* Mice
* Oocytes
* Ovulation
* Proteome
* RNA, Messenger
* RNA-Binding Proteins
* Spindle Apparatus
|keywords=* RNA dynamics
* aging
* centromere
* gene expression
* histone pattern
* maternal effect genes
* oocyte
* spindle chromosome complex
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5853592
}}
{{medline-entry
|title=[[MDM2]] turnover and expression of [[ATRX]] determine the choice between quiescence and senescence in response to [[CDK4]] inhibition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25803170
|abstract=[[CDK4]] inhibitors ([[CDK4]]i) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers. However, not all tumors respond favorably to these drugs. [[CDK4]] activity is critical for progression through G1 phase and into the mitotic cell cycle. Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state. In this report, using well-differentiated and dedifferentiated liposarcoma (WD/DDLS) cell lines, we show that the proteolytic turnover of [[MDM2]] is required for [[CDK4]]i-induced senescence. Failure to reduce [[MDM2]] does not prevent [[CDK4]]i-induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state. Reducing [[MDM2]] in these cells drives them into the more stable senescent state. [[CDK4]]i-induced senescence associated with loss of [[MDM2]] is also observed in some breast cancer, lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which [[MDM2]] is overexpressed or in cells that contain wild type p53. [[MDM2]] turnover depends on its E3 ligase activity and expression of [[ATRX]]. Interestingly, in seven patients the changes in [[MDM2]] expression were correlated with outcome. These insights identify [[MDM2]] and [[ATRX]] as new regulators controlling geroconversion, the process by which quiescent cells become senescent, and this insight may be exploited to improve the activity of [[CDK4]]i in cancer therapy.
|mesh-terms=* Breast Neoplasms
* Cell Line, Tumor
* Cellular Senescence
* Cyclin-Dependent Kinase 4
* DNA Helicases
* Gene Knockdown Techniques
* Humans
* Liposarcoma
* Nuclear Proteins
* Phosphorylation
* Piperazines
* Proto-Oncogene Proteins c-mdm2
* Pyridines
* Retinoblastoma Protein
* X-linked Nuclear Protein
|keywords=* ATRX
* CDK4 inhibitors
* MDM2
* geroconversion
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480747
}}
{{medline-entry
|title=Atrx deficiency induces telomere dysfunction, endocrine defects, and reduced life span.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23563309
|abstract=Human [[ATRX]] mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres and pericentromeric heterochromatin, which is exacerbated by loss of p53 and linked to [[ATM]] activation. [[ATRX]]-deficient neuroprogenitors exhibited higher incidence of telomere fusions and increased sensitivity to replication stress-inducing drugs. Treatment of Atrx-null neuroprogenitors with the G-quadruplex (G4) ligand telomestatin increased DNA damage, indicating that [[ATRX]] likely aids in the replication of telomeric G4-DNA structures. Unexpectedly, mutant mice displayed reduced growth, shortened life span, lordokyphosis, cataracts, heart enlargement, and hypoglycemia, as well as reduction of mineral bone density, trabecular bone content, and subcutaneous fat. We show that a subset of these defects can be attributed to loss of [[ATRX]] in the embryonic anterior pituitary that resulted in low circulating levels of thyroxine and IGF-1. Our findings suggest that loss of [[ATRX]] increases DNA damage locally in the forebrain and anterior pituitary and causes tissue attrition and other systemic defects similar to those seen in aging.
|mesh-terms=* Aging
* Animals
* Bone and Bones
* Brain
* Cognition Disorders
* DNA Damage
* DNA Helicases
* Female
* Fibroblasts
* G-Quadruplexes
* Genotype
* Heterochromatin
* Insulin-Like Growth Factor I
* Ligands
* Longevity
* Male
* Mice
* Mice, Transgenic
* Microscopy, Fluorescence
* Nuclear Proteins
* Oxazoles
* Phenotype
* Stem Cells
* Telomere
* Thyroxine
* X-linked Nuclear Protein

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635723
}}
{{medline-entry
|title=Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/22367537
|abstract=Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to [[MYCN]] amplification (20%) and [[ALK]] activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, [[PTPRD]] and [[CSMD1]], which are involved in neuronal growth cone stabilization. In addition, [[ATRX]], [[TIAM1]] and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry [[MYCN]] amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
|mesh-terms=* Aging
* Chromosomes, Human
* Cluster Analysis
* DNA Helicases
* DNA Mutational Analysis
* Gene Expression Regulation, Neoplastic
* Genome, Human
* Growth Cones
* Guanine Nucleotide Exchange Factors
* Humans
* Mutation
* Neoplasm Staging
* Neurites
* Neuroblastoma
* Nuclear Proteins
* Prognosis
* T-Lymphoma Invasion and Metastasis-inducing Protein 1
* X-linked Nuclear Protein
* rac GTP-Binding Proteins
* rho GTP-Binding Proteins

|full-text-url=https://sci-hub.do/10.1038/nature10910
}}
{{medline-entry
|title=Frequency of replication/transcription errors in (A)/(T) runs of human genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/11479734
|abstract=To estimate the error rate of the gene expression machinery and its possible age-related increase, we compared the occurrence of polymerase errors during replication and transcription in (A)/(T) runs, in DNA and RNA of young and old individuals and of early- and late-passage cultured fibroblasts. We analyzed three human genes: TPRD, [[TGFBR2]], and [[ATRX]] containing stretches of (A)8, (A)10, and (T)13, respectively. The error rate was determined by sequencing 100 cloned PCR or RT-PCR fragments from each DNA and RNA sample. The error rates in replication and transcription increased with the stretch length. The pooled error rates for genomic DNA were: TPRD (A)8, [[TGFBR2]] (A)10, and [[ATRX]] (T)13: 1% /-0.41, 15.8% /-1.3, and 31.3% /-2.9, while those for RNA were: 3.8% /-0.5, 19.3% /-2.1, and 54.3% /-1.8, respectively. The deletions of one nucleotide were the most frequent errors. In the replication analysis, a significant difference was found in old versus young individuals for the [[ATRX]] (T)13. In the transcription analysis, significantly higher error rates were obtained in old versus young individuals for the TPRD (A)8 and [[TGFBR2]] (A)10. For these genes, the error rate in RNA isolated from fibroblasts was significantly higher than that in blood. The data show a trend of age-related increase in replication/transcription errors; however further studies are necessary to confirm this hypothesis, since the sample size is small. This imperfect fidelity of the gene expression process may explain the evolutionary disadvantage of nucleotide repeats within coding sequences, and that these repeats are targets for mutations in human diseases.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Base Sequence
* Cell Line
* DNA
* DNA Damage
* DNA Helicases
* DNA Primers
* DNA Replication
* DNA-Binding Proteins
* Female
* Genome, Human
* Humans
* Mutation
* Nuclear Proteins
* Protein-Serine-Threonine Kinases
* Proteins
* RNA
* Receptor, Transforming Growth Factor-beta Type II
* Receptors, Transforming Growth Factor beta
* Repetitive Sequences, Nucleic Acid
* Transcription Factors
* Transcription, Genetic
* X-linked Nuclear Protein

|full-text-url=https://sci-hub.do/10.1007/s004390100541
}}