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)

Bloom syndrome is a rare autosomal recessive genetic disorder characterized by lupus-like erythematous telangiectasias of the face, sun sensitivity, stunted growth, and immunodeficiency. Chromosome instability syndromes have a common feature, being associated at high frequency with neoplasia. BS is considered as one of the chromosome instability syndromes since the fibroblasts or lymphocytes of BS patients show excessive spontaneous chromosome instability. The causative gene of BS (BLM) was identified as a RecQ helicase homologue. In this review, we showed the characteristic phenotypes of BS, especially two Japanese siblings. In the latter of the review, the functional domains of BLM, those are nuclear localization signal and the interacting proteins such as ATM, are shown. Several lines of reports indicates that BLM helicase is involved in the re-initiation of DNA replication at sites where replication forks have arrested or collapsed. To elucidate the precise function of RecQ helicase in DNA repair and replication aims not only to improve our understanding of the molecular basis for tumorigenesis, but also to extend the range of potential therapeutic targets.
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PMID:The function of RecQ helicase gene family (especially BLM) in DNA recombination and joining. 1549 27

The BLM helicase, a deficiency that markedly increases cancer incidence in humans, is required for optimal repair during DNA replication. We show that BLM rapidly moves from PML nuclear bodies to damaged replication forks, returning to PML bodies several hours later, owing to activities of the DNA damage response kinases ATR and ATM, respectively. Immunofluorescence and cellular fractionation demonstrate that BLM partitions to different sub-cellular compartments after replication stress. Unexpectedly, fibroblasts lacking BLM were deficient in phospho-ATM (S-1981) and 53-binding protein-1 (53BP1), and these proteins failed to form foci following replication stress. Expression of a dominant p53 mutant or helicase-deficient BLM restored replication stress-induced 53BP1 foci, but only mutant p53 restored optimal ATM activation. Thus, optimal repair of damaged replication fork lesions likely requires both ATR and ATM. BLM recruits 53BP1 to these lesions independent of its helicase activity, and optimal activation of ATM requires both p53 and BLM helicase activities.
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PMID:ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation. 1553 48

DNA damage surveillance networks in human cells can activate DNA repair, cell cycle checkpoints and apoptosis in response to fewer than four double-strand breaks (DSBs) per genome. These same networks tolerate telomeres, in part because the protein TRF2 prevents recognition of telomeric ends as DSBs by facilitating their organization into T loops. We now show that TRF2 associates with photo-induced DSBs in nontelomeric DNA in human fibroblasts within 2 s of irradiation. Unlike gammaH2AX, a common marker for DSB damage, TRF2 forms transient foci that colocalize closely with DSBs. The TRF2 DSB response requires the TRF2 basic domain but not its Myb domain and occurs in the absence of functional ATM and DNA-PK protein kinases, MRE11/Rad50/NBS1 complex and Ku70, WRN and BLM repair proteins. Furthermore, overexpression of TRF2 inhibits DSB-induced phosphorylation of ATM signaling targets. Our results implicate TRF2 in an initial stage of DSB recognition and processing that occurs before association of ATM with DSBs and activation of the ATM-dependent DSB response network.
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PMID:Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. 1753 57

Phosphorylation of p53 on serine 15 by ATM or ATR is a frequent modification and initiates a cascade of post-translational modifications. To identify possible mechanisms that modulate p53 functions in recombination surveillance, we compared the nuclear localization of p53 phosphorylated on serine 15 (p53pSer15) and the key enzymes of homologous recombination (HR) after replication fork stalling. We demonstrate an almost mutually exclusive subcompartmentalization with Rad52, while p53pSer15 was colocalizing with 40-60% of the Rad51 and Mre11 foci. Therefore, possible sites of p53pSer15-dependent regulation seem to be sites of Rad51- rather than Rad52-dependent HR processes. Remarkably, the association of p53pSer15 with repair complexes containing Rad51 or Mre11 was transient, because less than 20% of the Rad51 and Mre11 foci overlapped with p53pSer15 after 6 h. When we examined colocalization and co-immunoprecipitation of p53pSer15 and the RecQ helicase BLM with recombination surveillance and proapoptotic functions, we observed colocalization within a fraction of approximately 70% of the BLM foci and stable physical interactions until 6 h after replication arrest. Our data suggest that p53pSer15 plays a dual role in the functional interactions with early complexes of Rad51-dependent recombination and with BLM-associated surveillance and signalling complexes within distinct nuclear subcompartments.
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PMID:Differences in the association of p53 phosphorylated on serine 15 and key enzymes of homologous recombination. 1580 45

Renal angiotensin II (AII) is suggested to play a role in the enhanced sodium reabsorption that causes a shift in pressure natriuresis in obesity related hypertension; however, the mechanism is not known. Therefore, to assess the influence of AII on tubular sodium transport, we determined the effect of AII on the Na+, K+-ATPase activity (NKA), an active transporter regulated by the AT1 receptor activity, in the isolated proximal tubules of lean and obese Zucker rats. Also, we determined the levels of the tubular AT1 receptor and associated signal transducing G proteins, as the initial signaling components that mediate the effects of AII on Na+, K+-ATPase activity. In the isolated proximal tubules, AII produced greater stimulation of the NKA activity in obese compared with lean rats. Determination of the AT1 receptors by Scatchard analysis of the [125I] Sar-Ang II binding and Western blot analysis in the basolateral (BLM) and brush border membrane (BBM) revealed a modest but significant increase (23%) in the AT1 receptor number mainly in the BLM of obese compared with lean rats. The AII affinity for AT1 receptors, as determined by IC50 values of AII to displace [125I] Sar-Ang II binding in BLM and BBM were similar in lean and obese rats. Western blot analysis revealed significant increases in Gialpha1, Gialpha2, Gialpha3, and Gq/11alpha in BLM and Gialpha1, Gialpha3, and Gq/11alpha in BBM of obese as compared with lean rats. The increase in the levels of the AT1 receptor and G proteins, mainly in the BLM, may be contributing to the enhanced AII-induced activation of NKA in the proximal tubules of obese rats. This phenomenon, in part, may be responsible for the increased sodium reabsorption and the development of hypertension in obese Zucker rats.
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PMID:Enhanced angiotensin II-induced activation of Na+, K+-ATPase in the proximal tubules of obese Zucker rats. 1644 62

Stalled replication forks induce p53, which is required to maintain the replication checkpoint. In contrast to the well-established mechanisms of DNA damage-activated p53, the downstream effectors and upstream regulators of p53 during replication blockade remain to be deciphered. Hydroxyurea triggered accumulation of p53 through an increase in protein stability. The requirement of p53 accumulation for the replication checkpoint was not due to p21(CIP1/WAF1) as its down-regulation with short-hairpin RNA did not affect the checkpoint. Similar to DNA damage, stalled replication triggered the activation of the MRN-ataxia telangiectasia mutated (ATM)/ATM and Rad3-related-CHK1/CHK2 axis. Down-regulation of CHK1 or CHK2, however, reduced p53 basal expression but not the hydroxyurea-dependent induction. Moreover, p53 was still stabilized in ataxia telangiectasia cells or in cells treated with caffeine, suggesting that ATM was not a critical determinant. These data also suggest that the functions of ATM, CHK1, and CHK2 in the replication checkpoint were not through the p53-p21(CIP1/WAF1) pathway. In contrast, induction of p53 by hydroxyurea was defective in cells lacking NBS1 and BLM. In this connection, the impaired replication checkpoint in several other genetic disorders has little correlation with the ability to stabilize p53. These data highlighted the different mechanisms involved in the stabilization of p53 after DNA damage and stalled replication forks.
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PMID:Stalled replication induces p53 accumulation through distinct mechanisms from DNA damage checkpoint pathways. 1648 26

A rare genetic disease, Fanconi anemia (FA), now attracts broader attention from cancer biologists and basic researchers in the DNA repair and ubiquitin biology fields as well as from hematologists. FA is a chromosome instability syndrome characterized by childhood-onset aplastic anemia, cancer or leukemia susceptibility, and cellular hypersensitivity to DNA crosslinking agents. Identification of 11 genes for FA has led to progress in the molecular understanding of this disease. FA proteins, including a ubiquitin ligase (FANCL), a monoubiquitinated protein (FANCD2), a helicase (FANCJ/BACH1/BRIP1), and a breast/ovarian cancer susceptibility protein (FANCD1/BRCA2), appear to cooperate in a pathway leading to the recognition and repair of damaged DNA. Molecular interactions among FA proteins and responsible proteins for other chromosome instability syndromes (BLM, NBS1, MRE11, ATM, and ATR) have also been found. Furthermore, inactivation of FA genes has been observed in a wide variety of human cancers in the general population. These findings have broad implications for predicting the sensitivity and resistance of tumors to widely used anticancer DNA crosslinking agents (cisplatin, mitomycin C, and melphalan). Here, we summarize recent progress in the molecular biology of FA and discuss roles of the FA proteins in DNA repair and cancer biology.
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PMID:Molecular pathogenesis of Fanconi anemia: recent progress. 1649 6

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

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

Bloom syndrome (BS) is a rare human autosomal recessive disorder characterized by marked genetic instability associated with greatly increased predisposition to a wide range of cancers affecting the general population. BS arises through mutations in both copies of the BLM gene which encodes a 3'-5' DNA helicase identified as a member of the RecQ family. Several studies support a major role for BLM in the cellular response to DNA damage and stalled replication forks. However, the specific function(s) of BLM remain(s) unclear. The BLM protein is strongly expressed and phosphorylated during mitosis, but very little information is available about the origin and the significance of this phosphorylation. We show here that ATM kinase provides only a limited contribution to the mitotic phosphorylation of BLM. We also demonstrate that BLM is directly phosphorylated at multiple sites in vitro by the mitotic cdc2 kinase, and identify two new sites of mitotic BLM phosphorylation: Ser-714 and Thr-766. Our results identify BLM helicase as a new substrate for cdc2, which may have potential physiological implications for the role of BLM in mitosis.
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PMID:The Bloom syndrome helicase is a substrate of the mitotic Cdc2 kinase. 1688 Jul 35


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