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)

Caffeine inhibits ATM and ATR, two important checkpoint regulators, abolishes ionizing radiation-induced checkpoint response, and radiosensitizes cells. Radiation-induced DNA double-strand breaks (DSBs) are repaired by two major processes, homologous recombination repair (HRR) and nonhomologous end joining (NHEJ). It remains unclear which repair process, HRR or NHEJ, is affected when the checkpoint responses are abolished by caffeine. In this study we observed the effect of caffeine on gene-targeted DT40 chicken lymphoblast cells. We show that caffeine efficiently abolishes S- and G(2)-phase checkpoint responses after irradiation in all cell lines tested and greatly radiosensitizes wild-type and ATM(-/-) cells, the partially checkpoint-deficient cells. However, caffeine has a much smaller radiosensitizing effect on RAD54(-/-) cells and has no effect on RAD51-deficient cells. RAD51 and RAD54 are the important factors for HRR. Our results indicate that the checkpoint responses abolished by caffeine (S and G(2)) mainly affect HRR, which results in cell radiosensitization.
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PMID:Caffeine could not efficiently sensitize homologous recombination repair-deficient cells to ionizing radiation-induced killing. 1260 Feb 45

The BRCA1 gene was isolated in 1994; germline mutations of this gene are known to confer susceptibility to breast and ovarian cancer in high-risk families. Since its discovery, several mutations have been identified in this gene; these are scattered throughout the gene, and include insertion and deletion frameshifts, base substitutions, and inferred regulatory mutations. It role in the pathogenesis of breast cancer, which accounts for almost 95%, although unproven to date, cannot be ruled out. The functional inactivation of both copies of this gene in sporadic tumor cells does not follow the traditional mode: the loss of function in BRCA1 is not accompanied by underlying mutation of the gene in tumor cells with loss of heterozygosity for the BRCA1 gene. Several studies now suggest that an alternate mechanism of inactivation, involving promoter hypermethylation that results in reduced expression of the gene, may be common to a significant proportion of sporadic breast and ovarian cancers. BRCA1 as a tumor suppressor plays an important role in maintaining genomic stability. BRCA1 has the ability to interact with numerous proteins and to form complexes that are involved in recognizing and subsequently repairing DNA. BRCA1 contains several functional domains that directly or indirectly interact with a variety of proteins via protein-protein interaction; these include tumor suppressors (BRCA2, p53, Rb and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell cycle regulators (cyclins and cyclin dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtIP), DNA damage-sensing complex and mismatch repair proteins (BRCA1- Associated Surveillance Complex; BASC) and signal transducer and activator of transcription (STAT) among others Formation of foci containing BRCA1 by inherited mutations, or epigenetic mechanisms (promoter methylation) in sporadic cancers leads to a loss of DNA repair ability, disrupts the potential to form complexes with other proteins that are crucial for DNA repair pathways. Thus, BRCA1 plays a significant role in maintaining genomic stability and serves as a tumor suppressor in breast cancer tumorigenesis.
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PMID:BRCA1 in cancer, cell cycle and genomic stability. 1295 14

Bloom's syndrome (BS) is a human genetic disorder associated with cancer predisposition. The BS gene product, BLM, is a member of the RecQ helicase family, which is required for the maintenance of genome stability in all organisms. In budding and fission yeasts, loss of RecQ helicase function confers sensitivity to inhibitors of DNA replication, such as hydroxyurea (HU), by failure to execute normal cell cycle progression following recovery from such an S-phase arrest. We have examined the role of the human BLM protein in recovery from S-phase arrest mediated by HU and have probed whether the stress-activated ATR kinase, which functions in checkpoint signaling during S-phase arrest, plays a role in the regulation of BLM function. We show that, consistent with a role for BLM in protection of human cells against the toxicity associated with arrest of DNA replication, BS cells are hypersensitive to HU. BLM physically associates with ATR (ataxia telangiectasia and rad3(+) related) protein and is phosphorylated on two residues in the N-terminal domain, Thr-99 and Thr-122, by this kinase. Moreover, BS cells ectopically expressing a BLM protein containing phosphorylation-resistant T99A/T122A substitutions fail to adequately recover from an HU-induced replication blockade, and the cells subsequently arrest at a caffeine-sensitive G(2)/M checkpoint. These abnormalities are not associated with a failure of the BLM-T99A/T122A protein to localize to replication foci or to colocalize either with ATR itself or with other proteins that are required for response to DNA damage, such as phosphorylated histone H2AX and RAD51. Our data indicate that RecQ helicases play a conserved role in recovery from perturbations in DNA replication and are consistent with a model in which RecQ helicases act to restore productive DNA replication following S-phase arrest and hence prevent subsequent genomic instability.
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PMID:Phosphorylation of the Bloom's syndrome helicase and its role in recovery from S-phase arrest. 1472 72

We evaluate here whether RAD51 and its paralogues XRCC2 and XRCC3 act via a common pathway for sensitivity to genotoxic stress, centrosome fragmentation and chromosome stability. We expressed the RAD51 dominant-negative SMRAD51 in irs1 and irs1SF cells, defective for XRCC2 and XRCC3, respectively, and in their corresponding wild-type cells (V79 and AA8, respectively). V79-SMRAD51 cells are sensitive to mitomycin C (MMC), but SMRAD51 did not further sensitize irs1 cells to MMC, showing that SMRAD51 and XRCC2 act on the same pathway for resistance to MMC. However, in contrast to irs1 and irs1SF cells, SMRAD51-V79 and SMRAD51-AA8 cells are not sensitive to gamma-rays or UV-C. Despite these differences in sensitivity, SMRAD51-expressing cells and xrcc2- or xrcc3-defective cells show similar increased levels of centrosome fragmentation. This spontaneous centrosome fragmentation is resistant to caffeine, suggesting that ATM and ATR are not involved. Consistent with centrosome fragmentation, increased aneuploidy was measured in irs1 and SMRAD51-expressing cells. Expression of SMRAD51 in irs1 or irs1SF cells did not increase further the frequency of multipolar cells. Thus, RAD51, XRCC2 and XRCC3 act in the same pathway for centrosome fragmentation, independently of the sensitivity to exogenous genotoxic stresses and of the ATM/ATR pathway.
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PMID:Genetic interactions between RAD51 and its paralogues for centrosome fragmentation and ploidy control, independently of the sensitivity to genotoxic stresses. 1578 36

Increased cell killing after exposure to low acute doses of X rays (0-0.5 Gy) has been demonstrated in cells of a number of human tumor cell lines. The mechanisms underlying this effect have been assumed to be related to a threshold dose above which DNA repair efficiency or fidelity increases. We have used cells of two radioresistant human tumor cell lines, one that shows increased sensitivity to low radiation doses (T98G) and one that does not (U373), to investigate the DNA damage response at low doses in detail and to establish whether there is a discontinuous dose response or threshold in activation of any important mediators of this response. In the two cell lines studied, we found a sensitive, linear dose response in early signaling and transduction pathways between doses of 0.1 and 2 Gy with no evidence of a threshold dose. We demonstrate that ATM-dependent signaling events to downstream targets including TP53, CHK1 and CHK2 occur after doses as low as 0.2 Gy and that these events promote an effective damage response. Using chemical inhibition of specific DNA repair enzymes, we show that inhibition of DNA-PK-dependent end joining has relatively little effect at low (<1 Gy) doses in hyper-radiosensitive cells and that at these doses the influence of RAD51-mediated repair events may increase, based on high levels of RAD51/BRCA2 repair foci. These data do not support a threshold model for activation of DNA repair in hyper-radiosensitive cells but do suggest that the balance of repair enzyme activity may change at low doses.
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PMID:DNA damage responses at low radiation doses. 1613 2

In response to DNA breaks, human cells delay their progression through the G1, S, and G2 phases of the cell cycle. This response requires the coordinated effort of the ATM-CHK2-p53 and ATR-CHK1 DNA damage-sensing pathways and DNA repair (eg, DNA-PK and RAD51 complexes). The turnover of many of these DNA damage-associated proteins is controlled by the 26S proteasome. In this article, we review molecular strategies that target each of these pathways using silencing RNA (siRNA), antisense, or small-molecule inhibition. Although these agents can radiosensitize tumor cells, little data are available regarding potential effects on normal tissues to determine the potential therapeutic ratio of these strategies after fractionated radiotherapy. Clinical trials using such agents will require novel correlative science endpoints to track DNA repair and cell-cycle arrest and will need careful assessment of normal tissue toxicity and stability.
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PMID:Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome. 1637 7

FA is a rare genetic disorder characterized by developmental abnormalities, bone marrow failure and cancer susceptibility. Cells that are derived from patients with FA display spontaneous chromosomal instability and hypersensitivity to DNA crosslinking agents that is used in FA clinical diagnostics. FA is genetically heterogeneous and caused by mutations in at least 11 distinct genes, FANCA, FANCA, B, C, D1, D2, E, F, G, I, J and L. FA proteins interact with various proteins involved in DNA damage response and cell cycle checkpoint regulation, such as: RAD51, BRCA1, BRCA2, ATM or NBS1. Moreover, BRCA2 that plays a crucial role in homologous recombination is one of FA proteins. Collectively, all these data indicate, that the FA pathway is involved in different molecular processes that prevent DNA and control genomic stability, although its precise role still remains undefined.
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PMID:[Complex role of the FA proteins in providing genome stability]. 1667 73

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital abnormalities, progressive bone marrow failure, and cancer susceptibility. FA cells are hypersensitive to DNA crosslinking agents. FA is a genetically heterogeneous disease with at least 11 complementation groups. The eight cloned FA proteins interact in a common pathway with established DNA-damage-response proteins, including BRCA1 and ATM. Six FA proteins (A, C, E, F, G, and L) regulate the monoubiquitination of FANCD2 after DNA damage by crosslinking agents, which targets FANCD2 to BRCA1 nuclear foci containing BRCA2 (FANCD1) and RAD51. Some forms of hexavalent chromium [Cr(VI)] are implicated as respiratory carcinogens and induce several types of DNA lesions, including DNA interstrand crosslinks. We have shown that FA-A fibroblasts are hypersensitive to both Cr(VI)-induced apoptosis and clonogenic lethality. Here we show that Cr(VI) treatment induced monoubiquitination of FANCD2 in normal human fibroblasts, providing the first molecular evidence of Cr(VI)-induced activation of the FA pathway. FA-A fibroblasts demonstrated no FANCD2 monoubiquitination, in keeping with the requirement of FA-A for this modification. We also found that Cr(VI) treatment induced significantly more S-phase-dependent DNA double strand breaks (DSBs), as measured by gamma-H2AX expression, in FA-A fibroblasts compared to normal cells. However, and notably, DSBs were repaired equally in both normal and FA-A fibroblasts during recovery from Cr(VI) treatment. While previous research on FA has defined the genetic causes of this disease, it is critical in terms of individual risk assessment to address how cells from FA patients respond to genotoxic insult.
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PMID:FANCD2 monoubiquitination and activation by hexavalent chromium [Cr(VI)] exposure: activation is not required for repair of Cr(VI)-induced DSBs. 1689 75

Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
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PMID:Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. 1691 88

S-Adenosylmethionine decarboxylase (SAMDC) is a key enzyme for the biosynthesis of spermidine. SAMDC-suppressed HL-60 cells overproduced intracellular reactive oxygen species (ROS), which led to cell growth defect and partial cell death. ROS overproduction was caused by a decrease of the total glutathione (GSH) and the ratio of reduced to oxidized GSH, and by an increase of the intracellular iron uptake. When analyzed by real-time polymerase chain reaction, the transcripts of the genes involved in the GSH synthesis (gamma-glutamyl cysteine synthetase, GSH synthetase), as well as the gene of the GSH-reducing enzyme (NADP+-dependent isocitrate dehydrogenase), were decreased dramatically in these cells. DNA-repairing genes (ATM, PARP, RAD51 and MSH2) also were not activated transcriptionally. In these situations, excessive ROS induced severe DNA damage, which could not be repaired, and ultimately led the cells to a spontaneous cell death or an early senescence state. For such cells, gamma-radiation and cisplatin, which are direct DNA-damaging agents, were very effective for promoting cell death.
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PMID:S-Adenosylmethionine decarboxylase partially regulates cell growth of HL-60 cells by controlling the intracellular ROS level: Early senescence and sensitization to gamma-radiation. 1706 47


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