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)

Patients with the genetic disorder ataxia telangiectasia (AT) have mutations in the AT mutated (ATM) gene, which is homologous to TEL1 and the checkpoint gene MEC1. A tel1 deletion mutant, unlike a mec1 deletion, is viable and does not exhibit increased sensitivity to DNA-damaging agents. However, increased dosage of TEL1 rescues sensitivity of a mec1 mutant, mec1-1, to DNA-damaging agents and rescues viability of a mec1 disruption. mec1-1 tel1 delta 1 double mutants are synergistically sensitive to DNA-damaging agents, including radiomimetic drugs. These data indicate that TEL1 and MEC1 are functionally related and that functions of the ATM gene are apparently divided between at least two S. cerevisiae homologs.
 ...
PMID:TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. 754 45

Yeast chromosomes terminate in tracts of simple repetitive DNA (poly[G1-3T]). Mutations in the gene TEL1 result in shortened telomeres. Sequence analysis of TEL1 indicates that it encodes a very large (322 kDa) protein with amino acid motifs found in phosphatidylinositol/protein kinases. The closest homolog to TEL1 is the human ataxia telangiectasia gene.
 ...
PMID:TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. 767 10

Telomeres are maintained in germ line cells and immortal cell lines, but shorten with each cell division in most somatic cells. Blood lymphocytes from individuals with ataxia telangiectasia (AT) demonstrate an accelerated rate of telomere shortening and high levels of telomere associations. This accelerated loss of telomeres in somatic cells in AT could be due to either the loss of more telomeric DNA with every cell division or an increased rate of cell division. The gene for AT shares homology with the yeast TEL1 gene, in which mutations result in abnormally shortened telomeres. Thus, mutations in the gene for ataxia telangiectasia may also influence the ability of germ line cells and immortal cell lines to properly maintain telomere homeostasis. To investigate a possible defect of telomere maintenance in AT we have analyzed 8 simian virus 40 (SV40)-immortalized AT cell lines and twelve SV40-immortalized non-AT cell lines for both telomerase activity and telomere length. The results demonstrate that telomere length in AT cells is maintained via telomerase or an alternative (ALT) pathway in a manner indistinguishable from cell lines derived from normal cells. We also investigated telomere dynamics in one telomerase-positive AT cell line by analyzing the changes in the length of a single telomere, and found that this telomere maintained its equilibrium mean length (EML) similar to normal cell lines with stable chromosomes. The combined results show no significant differences between the telomeres of immortal AT and non-AT cell lines, demonstrating that the absence of wild-type ATM does not result in a fundamental defect in telomere maintenance in these cells.
 ...
PMID:Normal telomere maintenance in immortal ataxia telangiectasia cell lines. 935 46

The ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia, has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination and cell cycle control. The ATM gene has homology with the TEL1 gene of yeast, mutations of which lead to shortened telomeres. To test the hypothesis that the ATM gene product is involved in telomere metabolism, we examined telomeric associations (TA), telomere length, and telomerase activity in human cells expressing either dominant-negative or complementing fragments of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper (LZ) motif mimics that of ataxia telangiectasia (A-T) cells. These transfected RKO cells relative to transfected controls had a higher frequency of cells with TA and shortened telomeres, but no detectable change in telomerase activity. In addition, the percentage of cells with TA after gamma irradiation was higher in the transfected RKO cells with dominant negative activity of the ATM gene, compared to control cells. SV40 transformed fibroblasts derived from an A-T patient and transfected with a complementing carboxyl terminal kinase region of the ATM gene had a reduced frequency of cells with TA, with no effect on the telomere length or telomerase activity. The present studies using isogenic cells with manipulated ATM function demonstrate a role for the ATM gene product in telomere metabolism.
 ...
PMID:Influence of ATM function on telomere metabolism. 940 Sep 92

The Saccharomyces cerevisiae RAD9 checkpoint gene is required for transient cell-cycle arrests and transcriptional induction of DNA repair genes in response to DNA damage. Polyclonal antibodies raised against the Rad9 protein recognized several polypeptides in asynchronous cultures, and in cells arrested in S or G2/M phases while a single form was observed in G1-arrested cells. Treatment with various DNA damaging agents, i.e. UV, ionizing radiation or methyl methane sulfonate, resulted in the appearance of hypermodified forms of the protein. All modifications detected during a normal cell cycle and after DNA damage were sensitive to phosphatase treatment, indicating that they resulted from phosphorylation. Damage-induced hyperphosphorylation of Rad9 correlated with checkpoint functions (cell-cycle arrest and transcriptional induction) and was cell-cycle stage- and progression-independent. In asynchronous cultures, Rad9 hyperphosphorylation was dependent on MEC1 and TEL1, homologues of the ATR and ATM genes. In G1-arrested cells, damage-dependent hyperphosphorylation required functional MEC1 in addition to RAD17, RAD24, MEC3 and DDC1, demonstrating cell-cycle stage specificity of the checkpoint genes in this response to DNA damage. Analysis of checkpoint protein interactions after DNA damage revealed that Rad9 physically associates with Rad53.
 ...
PMID:The budding yeast Rad9 checkpoint protein is subjected to Mec1/Tel1-dependent hyperphosphorylation and interacts with Rad53 after DNA damage. 975 68

Telomeres, found at chromosomal ends, are essential for stable maintenance of linear chromosomes in eukaryotes. The ATM family of genes, including budding yeast TEL1 (refs 1,2), fission yeast rad3+ (ref. 3) and human ATM (ref. 4), have been reported to be involved in telomere length regulation, although the significance of the telomere phenotypes observed with the mutated genes remains elusive. We have cloned tel1+, another fission yeast ATM homologue, and found that a tel1rad3 double mutant lost all telomeric DNA sequences. Thus, the ATM homologues are essential in telomere maintenance. The mutant grew poorly and formed irregular-shaped colonies, probably due to chromosome instability, however, during prolonged culture of the double mutant, cells forming normal round-shaped colonies arose at a relatively high frequency. All three chromosomes in these derivative cells were circular and lacked telomeric sequences. To our knowledge, this is the first report of eukaryotic cells whose chromosomes are all circular. Upon meiosis, these derivative cells produced few viable spores. Therefore, the exclusively circular genome lacking telomeric sequences is proficient for mitotic growth, but does not permit meiosis.
 ...
PMID:Circular chromosome formation in a fission yeast mutant defective in two ATM homologues. 977 17

The ataxia telangiectasia (A-T) gene, ATM, predisposes affected homozygotes to a wide range of malignancies. It has been suggested that this is a consequence of the genomic instability associated with the syndrome. The elevated risk of malignancy is not, however, observed among A-T heterozygotes (except, apparently, regarding breast cancer). In this report we describe results from the study of the rare sporadic disease, T cell prolymphocytic leukaemia (T-PLL). In all individuals tested, we observed that at least one ATM allele was disrupted by rearrangement, that in many cases both alleles were disrupted and that there were additional mutations, predominantly missense, that clustered toward the 3' end of the gene corresponding to the protein's phosphatidylinositol 3-kinase (PIK)-related domain. We conclude that the ATM gene can act as a tumour suppressor in the development of sporadic T-PLL. Our finding of a surfeit of mutations within ATM may reflect the involvement of the gene at more than one step in tumorigenesis. In particular, we suggest that the clustering of missense mutations may pertain to the late-onset character of both sporadic and A-T-related T-PLL, since the closest homologue of Atm protein is the yeast TEL1 protein that maintains telomere length. ATM inactivation may not be the initiating event in T-PLL tumorigenesis: prior mutation of another gene--perhaps TCL1 activation--may be obligate. This would explain the recessive character of T-PLL risk in A-T.
 ...
PMID:The ataxia telangiectasia gene in familial and sporadic cancer. 1002 98

In the yeast Saccharomyces cerevisiae, chromosomes terminate with a repetitive sequence [poly(TG(1-3))] 350 to 500 bp in length. Strains with a mutation of TEL1, a homolog of the human gene (ATM) mutated in patients with ataxia telangiectasia, have short but stable telomeric repeats. Mutations of TLC1 (encoding the RNA subunit of telomerase) result in strains that have continually shortening telomeres and a gradual loss of cell viability; survivors of senescence arise as a consequence of a Rad52p-dependent recombination events that amplify telomeric and subtelomeric repeats. We show that a mutation in MEC1 (a gene related in sequence to TEL1 and ATM) reduces telomere length and that tel1 mec1 double mutant strains have a senescent phenotype similar to that found in tlc1 strains. As observed in tlc1 strains, survivors of senescence in the tel1 mec1 strains occur by a Rad52p-dependent amplification of telomeric and subtelomeric repeats. In addition, we find that strains with both tel1 and tlc1 mutations have a delayed loss of cell viability compared to strains with the single tlc1 mutation. This result argues that the role of Tel1p in telomere maintenance is not solely a direct activation of telomerase.
 ...
PMID:Interactions of TLC1 (which encodes the RNA subunit of telomerase), TEL1, and MEC1 in regulating telomere length in the yeast Saccharomyces cerevisiae. 1045 54

Homozygous mutations in the human ATM gene lead to a pleiotropic clinical phenotype of ataxia-telangiectasia (A-T) patients and correlating cellular deficiencies in cells derived from A-T donors. Saccharomyces cerevisiae tel1 mutants lacking Tel1p, which is the closest sequence homologue to the ATM protein, share some of the cellular defects with A-T. Through genetic complementation of A-T cells with the yeast TEL1 gene, we provide evidence that Tel1p can partially compensate for ATM in suppressing hyperrecombination, radiation-induced apoptosis, and telomere shortening. Complementation appears to be independent of p53 activation. The data provided suggest that TEL1 is a functional homologue of human ATM in yeast, and they help to elucidate different cellular and biochemical pathways in human cells regulated by the ATM protein.
 ...
PMID:The yeast TEL1 gene partially substitutes for human ATM in suppressing hyperrecombination, radiation-induced apoptosis and telomere shortening in A-T cells. 1093 Apr 57

The ATM (ataxia telangiectasia mutated) gene product has been implicated in mitogenic signal transduction, chromosome condensation, meiotic recombination, and cell cycle control. The human ATM protein shows similarity to several yeast and mammalian proteins involved in meiotic recombination and cell cycle progression. Because of the homology of the human ATM gene to the TEL1 and rad3 genes of yeast, it has been suggested that mutations in ATM could lead to defective telomere maintenance. Recently, we have shown that the ATM gene product, which is defective in the cancer-prone disorder ataxia telangiectasia (AT), influences chromosome end associations and telomere length. A possible hypothesis explaining these results is that the defective telomere metabolism in AT cells is due to altered interactions between the telomeres and the nuclear matrix. These interactions were examined in nuclear matrix halos prior to and after irradiation. A difference was observed in the ratio of soluble and matrix-associated telomeric DNA between cells derived from AT and normal individuals. Treatment with ionizing radiation affected the ratio of soluble and matrix-associated telomeric DNA only in the AT cells. To test the hypothesis that the ATM gene product is involved in interactions between telomeres and the nuclear matrix, such interactions were examined in human cells expressing either a dominant-negative effect or complementation of the ATM gene. The phenotype of RKO colorectal tumor cells expressing ATM fragments containing a leucine zipper motif mimics the altered interactions of telomere and nuclear matrix seen in AT cells. Fibroblasts from AT individuals transfected with a wild-type ATM gene had corrected telomere-nuclear matrix interactions. In experiments designed to determine whether there is a link between the altered telomere-nuclear matrix interactions and defective telomere movement and clustering, a significant difference was observed in the ratio of soluble compared to matrix-associated telomeric DNA sequences in meiocytes of Atm(-/-) and control mice. These results suggest that the ATM gene influences the interactions between telomeres and the nuclear matrix and that alterations in telomere chromatin could be at least partly responsible for the pleiotropic phenotypes of the ATM gene. This paper summarizes our recent publications on the influence of inactivation of ATM on the interaction of telomeres with nuclear matrix in somatic and germ cells.
 ...
PMID:Influence of ATM function on interactions between telomeres and nuclear matrix. 1093 83


1 2 3 Next >>