Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The TOR proteins, originally identified as targets of the immunosuppressant rapamycin, contain an ATM-like "lipid kinase" domain and are required for early G1 progression in eukaryotes. Using a screen to identify Saccharomyces cerevisiae mutants requiring overexpression of Tor1p for viability, we have isolated mutations in a gene we call ROT1 (requires overexpression of Tor1p). This gene is identical to DNA2, encoding a helicase required for DNA replication. As with its role in cell cycle progression, both the N-terminal and C-terminal regions, as well as the kinase domain of Tor1p, are required for rescue of dna2 mutants. Dna2 mutants are also rescued by Tor2p and show synthetic lethality with tor1 deletion mutants under specific conditions. Temperature-sensitive (Ts) dna2 mutants arrest irreversibly at G2/M in a RAD9- and MEC1-dependent manner, suggesting that Dna2p has a role in S phase. Frequencies of mitotic recombination and chromosome loss are elevated in dna2 mutants, also supporting a role for the protein in DNA synthesis. Temperature-shift experiments indicate that Dna2p functions during late S phase, although dna2 mutants are not deficient in bulk DNA synthesis. These data suggest that Dna2p is not required for replication fork progression but may be needed for a later event such as Okazaki fragment maturation.
Mol Biol Cell 1997 Dec
PMID:Characterization of Saccharomyces cerevisiae dna2 mutants suggests a role for the helicase late in S phase. 939 73

A human-mouse hybrid containing a human 11q22-23 fragment including the ATM locus was used to examine its capability to correct the cellular defect of ataxia-telangiectasia (A-T). Examination of 21 A-T-derived hybrids indicated that the acquired radioresistance was observed in the clones where the 11q22-23 fragment was transferred intact, but not in those where donor-derived 11q segment was lost. In one exceptional clone, the ATM locus was deleted from the transferred fragment, while it was still partially radioresistant. This partially radioresistant clone was found to include the mouse-derived fragment containing the Atm gene, the mouse homologue of human ATM gene. Similar association of partial radioresistance with the presence of mouse Atm gene was observed in three additional hybrids. The results indicate that the cellular A-T defect can be corrected by the mouse subchromosomal fragment containing the Atm gene as well as by the human 11q22-23 fragment containing the ATM gene, but apparently to a lesser extent in the former.
Somat Cell Mol Genet 1997 Sep
PMID:Phenotypic correction of ataxia-telangiectasia cellular defect by exogenously introduced human or mouse subchromosomal fragments. 954 77

Disruption of the mouse Atm gene, whose human counterpart is consistently mutated in ataxia-telangiectasia (A-T) patients, creates an A-T mouse model exhibiting most of the A-T-related systematic and cellular defects. While ATM plays a major role in signaling the p53 response to DNA strand break damage, Atm-/- p53(-/-) mice develop lymphomas earlier than Atm-/- or p53(-/-) mice, indicating that mutations in these two genes lead to synergy in tumorigenesis. The cell cycle G1/S checkpoint is abolished in Atm-/- p53(-/-) mouse embryonic fibroblasts (MEFs) following gamma-irradiation, suggesting that the partial G1 cell cycle arrest in Atm-/- cells following gamma-irradiation is due to the residual p53 response in these cells. In addition, the Atm-/- p21(-/-) MEFs are more severely defective in their cell cycle G1 arrest following gamma-irradiation than Atm-/- and p21(-/-) MEFs. The Atm-/- MEFs exhibit multiple cellular proliferative defects in culture, and an increased constitutive level of p21 in these cells might account for these cellular proliferation defects. Consistent with this notion, Atm-/- p21(-/-) MEFs proliferate similarly to wild-type MEFs and exhibit no premature senescence. These cellular proliferative defects are also rescued in Atm-/- p53(-/-) MEFs and little p21 can be detected in these cells, indicating that the abnormal p21 protein level in Atm-/- cells is also p53 dependent and leads to the cellular proliferative defects in these cells. However, the p21 mRNA level in Atm-/- MEFs is lower than that in Atm+/+ MEFs, suggesting that the higher level of constitutive p21 protein in Atm-/- MEFs is likely due to increased stability of the p21 protein.
Mol Cell Biol 1998 Jul
PMID:Involvement of p53 and p21 in cellular defects and tumorigenesis in Atm-/- mice. 963 22

Ataxia telangiectasia (A-T) is an autosomal recessive disorder with a broad range of clinical manifestations and a frequency of 1:40,000-100,000 live births. Epidemiological studies have suggested that A-T heterozygotes are at an elevated risk of breast cancer. ATM mutations occur worldwide over the entire ATM gene, making it difficult to identify heterozygotes in large populations. However, some founder-effect mutations are specific for certain populations. Here, we present four mutations in Costa Rican A-T patients that accounted for 86-93% of 41 patients studied in two batches. We have developed assays for rapid detection of these four mutations which can be used diagnostically. They will also enable the Costa Rican population to be used as a model for analyzing the role of ATM heterozygosity in cancer development and other disorders.
Mol Genet Metab 1998 May
PMID:A model for ATM heterozygote identification in a large population: four founder-effect ATM mutations identify most of Costa Rican patients with ataxia telangiectasia. 968 16

In budding yeast, DNA damage can activate a checkpoint surveillance system controlled by the RAD9, RAD53, and MEC1 genes, resulting in a delay in cell cycle progression. Here, I report that DNA damage induces rapid and extensive phosphorylation of Rad9p in a manner that correlates directly with checkpoint activation. This response is dependent on MEC1, which encodes a member of the evolutionarily conserved ATM family of protein kinases, and on gene products of the RAD24 epistasis group, which have been implicated in the recognition and processing of DNA lesions. Since the phosphorylated form of Rad9p appears capable of interacting stably with Rad53p in vivo, this phosphorylation response likely controls checkpoint signaling by Rad9p.
Mol Cell 1998 Aug
PMID:MEC1-dependent phosphorylation of Rad9p in response to DNA damage. 973 55

The identification of ATM , the gene responsible for the pleiotropic recessive disease ataxia telangiectasia, has initiated extensive research to determine the functions of its multifaceted protein product. The ATM protein belongs to a family of protein kinases that share similarities at their C-terminal region with the catalytic domain of phosphatidylinositol 3-kinases. Studies with ataxia telangiectasia (A-T) cells and Atm-deficient mice have shown that ATM is a key regulator of multiple signaling cascades which respond to DNA strand breaks induced by damaging agents or by normal processes, such as meiotic or V(D)J recombination. These responses involve the activation of cell cycle checkpoints, DNA repair and apoptosis. Other roles outside the cell nucleus might be carried out by the cytoplasmic fraction of ATM. In addition, ATM appears to function as a 'caretaker', suppressing tumorigenesis in specific T cell lineages.
Hum Mol Genet 1998
PMID:ATM: from gene to function. 973 76

The SAGA histone acetyltransferase/transcriptional adaptor complex is composed of multiple transcriptional regulators including Ada, Spt, and TAFII proteins. Here we identify an additional novel subunit of the complex, Tra1, an ATM/PI-3-kinase-related homolog of the human TRRAP cofactor, which is essential for c-Myc and E2F-mediated oncogenic transformation. Mass spectrometry, immunoblotting, and immunoprecipitation experiments confirm the stable association of this protein within SAGA. In addition, the Tra1 protein is a component of at least two other histone acetyltransferase protein complexes. These results indicate a role for Tra1 in the regulation of transcriptional activation through the recruitment of HAT activity to an activator-bound promoter.
Mol Cell 1998 Dec
PMID:The ATM-related cofactor Tra1 is a component of the purified SAGA complex. 988 73

PCAF histone acetylase is found in a complex with more than 20 associated polypeptides. Here we report cloning and characterization of the 400 kDa PCAF-associated factor referred to as PAF400. PAF400 is almost identical to TRRAP, which binds to c-Myc and E2F, and has significant sequence similarities to the ATM superfamily including FRAP, ATM, ATR, and the catalytic subunit of DNA-PK. Remarkably, PAF400 and FRAP share sequence similarity in broad regions that cover 80% of the entire PAF400 sequence. However, unlike the other members of the ATM superfamily, PAF400 is not a protein kinase as judged from the lack of kinase motif and autophosphorylation activity. We discuss the possibility that PAF400 may play a role in signaling of DNA damage to p53 by stimulation of p53 acetylation.
Mol Cell 1998 Dec
PMID:The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily. 988 74

Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.
Hum Mol Genet 1999 Jan
PMID:Characterization of ATM gene mutations in 66 ataxia telangiectasia families. 988 33

The gene mutated in ataxia telangiectasia (ATM) has an established tumour suppressor role in breast cancer. ATM appears to be expressed in most normal cells, including breast epithelium, where it has been postulated to have a nuclear role in cell cycle regulation following DNA damage. However, ATM is not upregulated after DNA damage. In this study, we demonstrate an absence of immunohistologically detectable levels of ATM in the normally quiescent myoepithelial cells that line normal breast ducts. This contrasts dramatically with the significant expression of ATM in the proliferative myoepithelium of sclerosing adenosis (n = 7). This upregulation of ATM suggests that ATM expression is coupled to the proliferative status of the myoepithelium. Our results also indicate that there are factors other than ATM gene mutations that can dramatically influence ATM expression in the breast and that these factors should be considered for their possible implications in carcinogenesis.
Mol Pathol 1998 Aug
PMID:Upregulation of ATM in sclerosing adenosis of the breast. 989 51


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