Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA topoisomerase II is involved in DNA topologic changes through the formation of a cleavable complex. This is stabilized by the antitumor drug VP16, which results in DNA breakage, aberrant recombination, and cell death. In this work, we compare the chromosomal damage induced by VP16 with that induced by bleomycin (BLM) in lymphoblasts from patients affected by the chromosome breakage syndromes ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and Bloom syndrome (BS), and by the progeroid syndromes Werner (WS) and Cockayne (CS). Patients affected by AT, XP, BS, and WS have a greatly enhanced risk of developing cancer. The results show that AF and WS cells are hypersensitive to VP16, as revealed in the higher proportion of metaphases showing exchange figures and more than two breaks. All lines except AT and one CS line showed normal sensitivity to BLM. Our data on the sensitivity to VP16 of all these mutant cells underline the fact that VP16 damage is amplified only in cells that have abnormal illegitimate recombination (i.e., AT and WS).
 ...
PMID:Effects of topoisomerase II inhibition in lymphoblasts from patients with progeroid and "chromosome instability" syndromes. 862 55

Genetic programs and age-dependent changes in DNA and protein are involved in aging. The genetic program governs body weight, longevity, aging rate, sex-maturating period and metabolic rate in mammals, and such a number of life history variables are highly correlated with body size. Monogenic age-1 and daf-2 C. elegans mutants extend life span twice. However, human monogenic progeroids shorten lifespan. The Werner syndrome gene was mapped in 8p12. Mutations in the Cockayne syndrome genes (the CSA and CSB genes acting for preferential repair of active genes by interacting with transcription factor TFIIH) and in the ataxia telangictasia gene ATM (homologous with PI-3 kinase for signal transduction) have been disclosed. All such findings suggest a strong basis for the genetic program of aging. In addition, recent evidence indicates that genetic instability, such as telomere loss, somatic and mitochondrial DNA mutations, increases with age. In addition, amounts of carbonylated protein also increase during human aging, and greatly increase in an SOD-deficient C. elegans mutant, but to a less extent in long-living age-1. Therefore, the aging process involves gene action, genetic instability and protein oxidation. Dietary restriction and elimination of deleterious excessive reactive oxygen species may improve many abnormalities due to aging.
 ...
PMID:[The mechanisms of aging and perspective for elimination of deleterious effects]. 889 Jun 1

Ataxia-telangiectasia (A-T) is a recessive human disease characterized by radiation sensitivity, genetic instability, immunodeficiency, and high cancer risk. We previously used expression cloning to identify CAT4.5, a human cDNA that partially suppresses multiple aspects of the A-T phenotype upon transfection into cultured cells. Sequencing CAT4.5 revealed a 1.1-kb intronic fragment followed by a related ORF of 2.5 kb that encodes the near full-length ORF for hTOP3, the first mammalian topoisomerase III to be identified. Endogenous expression of hTOP3 was found in all human tissues tested. Both pCAT4.5 and an antisense hTOP3 construct were able to inhibit spontaneous and radiation-induced apoptosis in A-T fibroblasts, whereas overexpression of a full-length hTOP3 cDNA did not. We postulate that topoisomerase III may be deregulated in A-T cells and that CAT4.5 complements the A-T phenotype via a dominant-negative mechanism. Furthermore, functional correction of hyper-recombination in A-T cells by CAT4.5 supports the hypothesis that the hTOP3 topoisomerase is involved in the control of genomic stability, perhaps in concert with the Bloom or Werner syndrome DNA helicases.
 ...
PMID:Overexpression of a truncated human topoisomerase III partially corrects multiple aspects of the ataxia-telangiectasia phenotype. 911 25

Most of the genes involved in the pathogenesis of the DNA replication and repair syndromes have now been cloned, and our understanding of the basis for the pleiotropic phenotype associated with many of these syndromes has rapidly and dramatically expanded. The elucidation of the specific interactions between proteins that comprise the transcription factor complex TFIIH raises the possibility that nucleotide excision repair, RNA polymerase II transcription, and cell cycle control are connected. Defects in the XPB, XPD, and XPG genes can result in three different syndromes, xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy, depending on the specific mutation involved. The recent cloning of the genes involved in Bloom syndrome (BLM) and Werner syndrome (WRN) show that both are DNA and RNA helicases with homology to each other and to other DExH box helicases, yet the mechanism by which defects in these genes cause such different phenotypes is not yet understood. The ataxia-telangiectasia gene (ATM) is involved in a variety of signal transduction pathways that regulate the cellular response to normal proliferative stimuli as well as the response to DNA damage, and the disruption of these signal transduction pathways provides an explanation for ataxia-telangiectasia characteristics such as ionizing radiation sensitivity, immunodeficiency, and infertility. Although the first Fanconi anemia gene (FAC) was cloned over 5 years ago, and a second Fanconi anemia gene (FAA) was cloned in 1996, the biochemical function of Fanconi anemia proteins largely remains a mystery. The recent construction of mutant mouse strains for several of these diseases should help unlock the difficult puzzle of the pathogenesis of these syndromes.
 ...
PMID:Disorders of DNA replication and repair. 942 94

Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development. The opposite viewpoint is most likely correct. Genetic drift occurs in finite populations and leads to homozygosity in multiple-alleled traits. Episodic selection events will alter random drift towards homozygosity in alleles that increase fitness with respect to the selection event. Aging increases population turnover, which accelerates the benefit of genetic drift. This advantage of aging led to the evolution of aging systems (ASs). Periodic predation was the most prevalent episodic selection pressure in evolution. Effective defenses to predation that allow exceptionally long lifespans to evolve are shells, extreme intelligence, isolation, and flight. Without episodic predation, aging provides no advantage and aging systems will be deactivated to increase reproductive potential in unrestricted environments. The periodic advantage of aging led to the periodic evolution of aging systems. Newer aging systems co-opted and added to prior aging systems. Aging organisms should have one dominant, aging system that co-opts vestiges of earlier-evolved systems as well as vestiges of prior systems. In human evolution, aging systems chronologically emerged as follows: telomere shortening, mitochondrial aging, mutation accumulation, senescent gene expression (AS#4), targeted somatic tissue apoptotic-atrophy (AS#5), and female reproductive tissue apoptotic-atrophy (AS#6). During famine or drought, to avoid extinction, reproduction is curtailed and aging is slowed or somewhat reversed to postpone or reverse reproductive senescence. AS#4-AS#6 are gradual and reversible aging systems. The life-extending/rejuvenating effects of caloric restriction support the idea of aging reversibility. Development and aging are timed by the gradual loss of cytosine methylation in the genome. Methylated cytosines (5mC) inhibit gene transcription, and deoxyribonucleic acid (DNA) cleavage by restriction enzymes. Cleavage inhibition prevents apoptosis, which requires DNA fragmentation. Free radicals catalyze the demethylation of 5mC while antioxidants catalyze the remethylation of cytosine by altering the activity of DNA methyltransferases. Hormones act as either surrogate free radicals by stimulating the cyclic adenosine monophosphate (cAMP) pathway or as surrogate antioxidants through cyclic guanosine monophosphate (cGMP) pathway stimulation. Access to DNA containing 5mC inhibited developmental and aging genes and restriction sites is allowed by DNA helicase strand separation. Tightly wound DNA does not allow this access. The DNA helicase generates free radicals during strand separation; hormones either amplify or counteract this effect. Caloric restriction slows or reverses the aging process by increasing melatonin levels, which suppresses reproductive and free radical hormones, while increasing antioxidant hormone levels. Cell apoptosis during CR leads to somatic wasting and a release of DNA, which increases bioavailable cGMP. The rapid aging diseases of progeria, the three diseases: (xeroderma pigmentosum (XP), Cockayne syndrome(CS), and ataxia telangiectasia (AT)), and Werner's syndrome are related to or caused by defects in three separate DNA helicases. The rapid aging diseases caused by mitochondrial malfunctions mirror those seen in XP, CS, and AT. Comparing these diseases allows for assignment of the different symptoms of aging to their respective aging systems. Follicle-stimulating hormone (FSH) demethylates the genes of AS#4, luteinizing hormone (LH) of AS#5, and estrogen of AS#6 while cortisol may act cooperatively with FSH and LH, and 5-alpha dihydrotestosterone (DHT) with FSH in these role. The Werner's DNA helicase links timing of the age of puberty, menopause, and maximum lifespan in one mechanism. Telomerase is under hormonal control. Most cancers likely result from malfunctions in the programmed apoptosis of AS#5 and AS#6. The Hayflick limit is reached primarily through loss of cytosine methylation of genes that inhibit replication. Men suffer the diseases of AS#4 at a higher rate than women who suffer from AS#5 more often. Adult mammal cloning suggests aging-related cellular demethylation, and thus aging, is reversible. This theory suggests that the protective effect of smoking and ibuprofen for Alzheimer's disease is caused through LH suppression.
 ...
PMID:The evolution of aging: a new approach to an old problem of biology. 979 99

Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by stunted growth, sun-sensitive erythema and immunodeficiency. Chromosomal abnormalities are often observed. Patients with BS are highly predisposed to cancers. The causative gene for BS has been identified as BLM. The former encodes a protein, which is a homologue of the RecQ DNA helicase family, a family which includes helicases such as Esherichia coli RecQ, yeast Sgs1, and human WRN. WRN is encoded by the gene that when mutated causes Werner's syndrome. The function of BLM in DNA replication and repair has not yet been determined, however. To understand the function of BLM in haematopoietic cells and the cause of immunodeficiency in BS, expression of the BLM gene in various human tissues and haematopoietic cell lines was analysed and the involvement of BLM in immunoglobulin rearrangement examined. In contrast to WRN, BLM was expressed strongly in the testis and thymus. B, T, myelomonocytic and megakaryocytic cell lines also expressed BLM. All of the examined sequences at the junction of the variable (V), diversity (D) and joining (J) regions of the immunoglobulin heavy-chain genes were in-frame, and N-region insertions were also present. The frequency of abnormal rearrangements of the T cell receptor was slightly elevated in the peripheral T cells of patients with BS compared with healthy individuals, whereas a higher frequency of abnormal rearrangements was observed in the cells of patients with ataxia-telangiectasia (A-T). In DND39 cell lines, the induction of sterile transcription, which is required for class switching of immunoglobulin heavy-chain constant genes, was correlated with the induction of the BLM gene. Taking into consideration all these results, BLM may not be directly involved in VDJ recombination, but is apparently involved in the maintenance of the stability of DNA.
 ...
PMID:Expression of the BLM gene in human haematopoietic cells. 1054 Jan 92

Breast cancer is considered to display a high degree of intratumor heterogeneity, without any obvious morphological and pathological steps to define sequential evolution, and its progression may vary among individual tumors. In an attempt to elucidate these etiological and phenotypic complexities, the present study, based on the fundamental concept that genomic instability is the engine of both tumor progression and tumor heterogeneity, was conducted to test the hypothesis that breast cancer pathogenesis is driven by double-strand break (DSB)-initiated chromosome instability (CIN). The rationale underlying this hypothesis is derived from the clues provided by family breast cancer syndromes, in which susceptibility genes, including p53, ATM, BRCA1 and BRCA2, are involved within the common functional pathway of DSB-related checkpoint/ repair. Because genomic deletion caused by DSB is reflected in the genetic mechanism of loss of heterozygosity (LOH), this genome-wide LOH study was conducted, using 100 tumors and 400 microsatellite markers. To minimize the effect of heterogeneity within tumors, the experimental technique of laser capture microdissection was used to ensure that genetic and phenotypic examinations were based on the same tumor cells. Support for our hypothesis comes from the observations that: (a) the extent of DSB-initiated CIN in tumors significantly increased as tumors progressed to poorer grades or later stages; (b) in the sequential steps toward CIN, the loci of p53 and ATM, the key checkpoint genes against DSB, were lost at the earliest stage; and (c) many loci identified to be important in breast tumorigenesis were the genomic sites possibly harboring the genes involved in DSB-related checkpoint/repair (including RAD51, RAD52, and BRCA1) or CIN (including FA-A, FA-D, and WRN), and a higher number of these loci showing LOH was significantly associated with increased level of DSB-initiated CIN (P < 0.0001). Breast cancers are thus considered to be sequentially progressive with CIN. However, CIN might also cause genetic heterogeneity, which was revealed by the findings that LOH at some markers was observed only in the component of ductal carcinoma in situ but not in the invasive component of the same tumors. In addition, some markers were found to preferentially lose at specific tumor grades, implying their contribution to genetic heterogeneity during tumor development. Therefore, this study suggests that breast cancer progression is clonal with regard to CIN, but different breast cancers would present distinct molecular profiles resulting from genetic heterogeneity caused by CIN.
 ...
PMID:Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. 1091 64

The average length of telomere repeats at the ends of chromosomes in most normal human somatic cells has been found to decrease by 50-200 base pairs with each cell division. The loss of telomere repeats has been causally linked to replicative senescence by the demonstration that overexpression of the enzyme telomerase can result in the elongation or maintenance of telomeres and immortalization of somatic cells with a diploid and apparently normal karyotype. Major questions that remain are related to the actual mechanism by which telomere shortening induces replicative senescence and the importance of telomere shortening and replicative senescence in the homeostasis of cells in renewal tissues and aging. This perspective is concerned with the consequences of telomere shortening at individual chromosomes in individual cells. Experimental evidence indicates that short telomeres accumulate prior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observations are compatible with limited repair of short telomeres by telomerase-dependent or telomerase-independent DNA repair pathways. Deficiencies in telomere repair may result in accelerated senescence and aging as well as genetic instability that facilitates malignant transformation. Examples of molecules that may have a role in the repair of telomeric DNA prior to replicative senescence include ATM, p53, PARP, DNA-PK, Ku70/80, the human hRad50-hMre11-p95 complex, BRCA 1 and 2 and the helicases implicated in Bloom's and Werner's syndrome.
 ...
PMID:Repair of telomeric DNA prior to replicative senescence. 1098 22

Chromosomal instability can occur when the DNA damage response and repair process fails, resulting in syndromes characterized by growth abnormalities, hematopoietic defects, mutagen sensitivity, and cancer predisposition. Mutations in ATM, NBS1, MRE11, BLM, WRN, and FANCD2 are responsible for ataxia telangiectasia (AT), Nijmegen breakage syndrome, AT-like disorder, Bloom and Werner syndrome, and Fanconi anemia group D2, respectively. This diverse group of disorders is thought to be linked through protein interactions with the breast cancer tumor susceptibility gene product, BRCA1. BRCA1 forms a multi-subunit protein complex referred to as the BRCA1-associated genome surveillance complex (BASC), which includes DNA damage repair proteins such as MSH2-MSH6 and MLH1, as well as ATM, NBS1, MRE11, and BLM. Although still controversial, this finding suggests similarities in the pathogenesis of the human chromosome breakage syndromes and a complementary role for each protein in DNA structure surveillance or damage repair.
 ...
PMID:Chromosomal breakage syndromes and the BRCA1 genome surveillance complex. 1173 19

Cancers arise as a result of genetic changes that impact upon cell proliferation through promoting cell division and/or inhibiting cell death. Tumour suppressor (TS) genes are the targets for many of these genetic changes. In general, both alleles of TS genes must be disrupted to observe a phenotypic effect. Broadly speaking, there are two types of TS gene: 'gatekeepers' and 'caretakers'. In contrast to gatekeepers, caretaker genes do not directly regulate proliferation, but act to prevent genomic instability. Thus, mutation of caretaker genes leads to accelerated conversion of a normal cell to a neoplastic cell. Many caretaker genes are required for the maintenance of genome integrity. This review focuses on those caretaker genes that play a role, directly or indirectly, in the repair of DNA strand breaks by the homologous recombination pathway, and that are associated with cancer-prone clinical syndromes, in particular ataxia telangiectasia, hereditary breast cancer, Bloom's syndrome and Werner's syndrome.
 ...
PMID:Caretaker tumour suppressor genes that defend genome integrity. 1192 76


<< Previous 1 2 3 4 5 6 7 8 9 Next >>