Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epigenetic control provides a mechanism for the reversible silencing of telomerase expression that occurs as a natural consequence of differentiation. Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis. Mutations in these pathways have been known to contribute to cancer formation. However, the incorporation of epigenetic regulatory mechanisms provides another line of defense against these negative occurrences. These proteins are also implicated in the process of senescence, caused in eukaryotic cell lines by telomere shortening. Although the debate continues, there is significant evidence to classify the process of cellular senescence as an in vitro model for human aging. In addition, the study of stem cells gives information about the down-regulation of hTERT in the aging process. Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment. Therefore, restoring telomerase activity as a putative therapeutic strategy necessitates further study to elucidate the intricacies linking genetic and epigenetic modulations of hTERT.
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PMID:Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems. 1576 67

Sgs1 is a RecQ family DNA helicase required for genome stability in Saccharomyces cerevisiae whose human homologs BLM, WRN, and RECQL4 are mutated in Bloom's, Werner, and Rothmund Thomson syndromes, respectively. Sgs1 and mismatch repair (MMR) are inhibitors of recombination between similar but divergent (homeologous) DNA sequences. Here we show that SGS1, but not MMR, is critical for suppressing spontaneous, recurring translocations between diverged genes in cells with mutations in the genes encoding the checkpoint proteins Mec3, Rad24, Rad9, or Rfc5, the chromatin assembly factors Cac1 or Asf1, and the DNA helicase Rrm3. The S-phase checkpoint kinase and telomere maintenance factor Tel1, a homolog of the human ataxia telangiectasia (ATM) protein, prevents these translocations, whereas the checkpoint kinase Mec1, a homolog of the human ATM-related protein, and the Rad53 checkpoint kinase are not required. The translocation structures observed suggest involvement of a dicentric intermediate and break-induced replication with multiple cycles of DNA template switching.
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PMID:Control of translocations between highly diverged genes by Sgs1, the Saccharomyces cerevisiae homolog of the Bloom's syndrome protein. 1680 76

Defects of DNA repair underlie genetic syndromes. Chromosomal aberrations and mutations might cause specific inborn defects. There are several syndromes with characteristic clinical features, which appear to be caused by chromosome instability which is a consequence of DNA repair defects. This article describe syndromes where hereditary mutations are the reason of chromosomal instability and cause serious clinical results: ataxia-telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, Fanconi's anemia, ICF syndrome, Roberts syndrome, dominantly inherited--PCD, Werner syndrome, xeroderma pigmentosum, Cockayne syndrome, trichothiodystrophy (TTD) and Rothmund-Thomson syndrome (RTS).
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PMID:[Chromosome instability syndromes]. 1687 67

Bloom syndrome (BS) is an autosomal recessive disorder characterized by a marked predisposition to cancer and elevated genomic instability. The defective protein in BS, BLM, is a member of the RecQ helicase family and is believed to function in various DNA transactions, including in replication, repair, and recombination. Here, we show that both endogenous and overexpressed human BLM accumulates at sites of laser light-induced DNA double-strand breaks within 10s and colocalizes with gammaH2AX and ATM. Like its RecQ helicase family member, WRN, the defective protein in Werner syndrome, dissection of the BLM protein revealed that its HRDC domain is sufficient for its recruitment to the damaged sites. In addition, we confirmed that the C-terminal region spanning amino acids 1250-1292 within the HRDC domain is necessary for BLM recruitment. To identify additional proteins required for the recruitment of BLM, we examined the recruitment of BLM in various mutants generated from chicken DT40 cells and found that the early accumulation of BLM was not dependent on the presence of ATM, RAD17, DNA-PKcs, NBS1, XRCC3, RAD52, RAD54, or WRN. Thus, HRDC domain in DNA helicases is a common early responder to DNA double-strand breaks, enabling BLM and WRN to be involved in DNA repair.
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PMID:BLM is an early responder to DNA double-strand breaks. 1687 11

Recentstudies have shown that wild-type and recombinant adeno-associated virus (AAV and rAAV) genomes persist in human tissue predominantly as double-stranded (ds) circular episomes derived from input linear single-stranded virion DNA. Using self-complementary recombinant AAV (scAAV) vectors, we generated intermediates that directly transition to ds circular episomes. The scAAV genome ends are palindromic hairpin-structured terminal repeats, resembling a double-stranded break repair intermediate. Utilizing this substrate, we found cellular DNA recombination and repair factors to be essential for generating circular episomal products. To identify the specific cellular proteins involved, the scAAV circularization-dependent vector was used as a reporter in 19 mammalian DNA repair-deficient cell lines. The results show that RecQ helicase family members (BLM and WRN), Mre11 and NBS1 of the Mre11-Rad50-Nbs1 (MRN) complex, and ATM are required for efficient scAAV genome circularization. We further demonstrated that the scAAV genome requires ATM and DNA-PK(CS), but not NBS1, to efficiently convert to a circular form in nondividing cells in vivo using transgenic mice. These studies identify specific pathways involved for further elucidating viral and cellular mechanisms of DNA maintenance important to the viral life cycle and vector utilizations.
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PMID:Host cell DNA repair pathways in adeno-associated viral genome processing. 1704 Dec 15

This review is focused on proteins with key roles in pathways controlling either reactive oxygen species or DNA damage responses, both of which are essential for preserving the nervous system. An imbalance of reactive oxygen species or inappropriate DNA damage response likely causes mutational or cytotoxic outcomes, which may lead to cancer and/or aging phenotypes. Moreover, individuals with hereditary disorders in proteins of these cellular pathways have significant neurological abnormalities. Mutations in a superoxide dismutase, which removes oxygen free radicals, may cause the neurodegenerative disease amyotrophic lateral sclerosis. Additionally, DNA repair disorders that affect the brain to various extents include ataxia-telangiectasia-like disorder, Cockayne syndrome or Werner syndrome. Here, we highlight recent advances gained through structural biochemistry studies on enzymes linked to these disorders and other related enzymes acting within the same cellular pathways. We describe the current understanding of how these vital proteins coordinate chemical steps and integrate cellular signaling and response events. Significantly, these structural studies may provide a set of master keys to developing a unified understanding of the survival mechanisms utilized after insults by reactive oxygen species and genotoxic agents, and also provide a basis for developing an informed intervention in brain tumor and neurodegenerative disease progression.
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PMID:Developing master keys to brain pathology, cancer and aging from the structural biology of proteins controlling reactive oxygen species and DNA repair. 1717 78

Werner syndrome (WS) is a premature aging syndrome caused by mutations of the WRN gene. Here, we demonstrate that a strain of WS fibroblast cells shows abnormal karyotypes characterized by several complex translocations and 50-fold more frequency of abnormal metaphases including dicentric chromosomes without fragments than normal cells when examined at a similar culture stage. Further, telomere fluorescence in situ hybridization indicates that the abnormal signals, extra telomere signal and loss of telomere signal, emerge two- to three-fold more frequently in WS cells than in normal cells. Taken together, these results indicate that chromosome instability including dysfunction of telomere maintenance is more prominent in WS cells than in normal cells. In addition, the accumulation of DNA double-strand breaks (DSBs) at the G(1) phase, including those at telomeres, detected by phosphorylated ATM (ataxia telangiectasia mutated) foci is accelerated in WS cells even at a low senescence level. The increased accumulation of DSBs in WS cells is reduced in the presence of anti-oxidative agents, suggesting that enhanced oxidative stress in WS cells is involved in accelerated accumulation of DSBs. These results indicate that WS cells are prone to accumulate DSBs spontaneously due to a defect of WRN, which leads to increased chromosome instability that could activate checkpoints, resulting in accelerated senescence.
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PMID:Increased chromosome instability and accumulation of DNA double-strand breaks in Werner syndrome cells. 1744 19

DNA alterations of every type are associated with the incidence of carcinogenesis, often on the genomic scale. Although homologous recombination (HR) is an important pathway of DNA repair, evidence is accumulating that deleterious genomic rearrangements can result from HR. It therefore follows that HR events may play a causative role in carcinogenesis. HR is elevated in response to carcinogens. HR may also be increased or decreased when its upstream regulation is perturbed or components of the HR machinery itself are not fully functional. This chapter summarizes research findings that demonstrate an association between HR and carcinogenesis. Increased or decreased frequencies of HR have been found in cancer cells and cancer-prone hereditary human disorders characterized by mutations in genes playing a role in HR, such as ATM, Tp53, BRCA, BLM, and WRN genes. Another evidence linking perturbations in HR and carcinogenesis is provided by studies showing that exposure to carcinogens results in an increased frequency of HR resulting in DNA deletions in yeast, human cells, or mice.
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PMID:Involvement of homologous recombination in carcinogenesis. 1745 46

The ends of chromosomes consist of a hexanucleotide DNA repeat sequence and specialized DNA-binding and telomere-associated proteins. An enzyme activity called telomerase maintains telomere length by using an RNA template (TR) and a reverse transcriptase (TERT) to add the hexanucleotide sequence to the free chromosome end. The structure of telomeres is maintained and modified by telomere repeat-binding factors (TRF1 and TRF2) and proteins known for their role in DNA damage responses, including poly(ADP-ribose) polymerase-1, Werner, and ATM. Telomerase activity can be quantified using a telomere repeat amplification protocol (TRAP) assay, and levels of TERT and telomere-associated proteins are evaluated by immunoblot and immunocytochemical methods. Levels of TERT and telomere-associated proteins can be overexpressed or knocked down using viral vector-based methods. Using the kinds of approaches described here, evidence has been obtained suggesting that telomeres play important roles in regulating neural stem cell proliferation, neuronal differentiation, senescence of glial cells, and apoptosis and DNA damage responses of neural cells.
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PMID:Telomere neurobiology. 1836 58

Werner syndrome (WS) is a human genetic disorder characterized by extensive clinical features of premature aging. Ataxia-telengiectasia (A-T) is a multisystem human genomic instability syndrome that includes premature aging in some of the patients. WRN and ATM, the proteins defective in WS and A-T, respectively, play significant roles in the maintenance of genomic stability and are involved in several DNA metabolic pathways. A role for WRN in DNA repair has been proposed; however, this study provides evidence that WRN is also involved in ATM pathway activation and in a S-phase checkpoint in cells exposed to DNA interstrand cross-link-induced double-strand breaks. Depletion of WRN in such cells by RNA interference results in an intra-S checkpoint defect, and interferes with activation of ATM as well as downstream phosphorylation of ATM target proteins. Treatment of cells under replication stress with the ATM kinase inhibitor KU 55933 results in a S-phase checkpoint defect similar to that observed in WRN shRNA cells. Moreover, gamma H2AX levels are higher in WRN shRNA cells than in control cells 6 and 16 h after exposure to psoralen DNA cross-links. These results suggest that WRN and ATM participate in a replication checkpoint response, in which WRN facilitates ATM activation in cells with psoralen DNA cross-link-induced collapsed replication forks.
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PMID:WRN is required for ATM activation and the S-phase checkpoint in response to interstrand cross-link-induced DNA double-strand breaks. 1859 39


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