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)

We report the identities of the members of a group of proteins that associate with BRCA1 to form a large complex that we have named BASC (BRCA1-associated genome surveillance complex). This complex includes tumor suppressors and DNA damage repair proteins MSH2, MSH6, MLH1, ATM, BLM, and the RAD50-MRE11-NBS1 protein complex. In addition, DNA replication factor C (RFC), a protein complex that facilitates the loading of PCNA onto DNA, is also part of BASC. We find that BRCA1, the BLM helicase, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci that contain PCNA when cells are treated with agents that interfere with DNA synthesis. The association of BRCA1 with MSH2 and MSH6, which are required for transcription-coupled repair, provides a possible explanation for the role of BRCA1 in this pathway. Strikingly, all members of this complex have roles in recognition of abnormal DNA structures or damaged DNA, suggesting that BASC may serve as a sensor for DNA damage. Several of these proteins also have roles in DNA replication-associated repair. Collectively, these results suggest that BRCA1 may function as a coordinator of multiple activities required for maintenance of genomic integrity during the process of DNA replication and point to a central role for BRCA1 in DNA repair.
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PMID:BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. 1078 65

Mutations in the gene ATM are responsible for the genetic disorder ataxia-telangiectasia (A-T), which is characterized by cerebellar dysfunction, radiosensitivity, chromosomal instability and cancer predisposition. Both the A-T phenotype and the similarity of the ATM protein to other DNA-damage sensors suggests a role for ATM in biochemical pathways involved in the recognition, signalling and repair of DNA double-strand breaks (DSBs). There are strong parallels between the pattern of radiosensitivity, chromosomal instability and cancer predisposition in A-T patients and that in patients with Nijmegen breakage syndrome (NBS). The protein defective in NBS, nibrin (encoded by NBS1), forms a complex with MRE11 and RAD50 (refs 1,2). This complex localizes to DSBs within 30 minutes after cellular exposure to ionizing radiation (IR) and is observed in brightly staining nuclear foci after a longer period of time. The overlap between clinical and cellular phenotypes in A-T and NBS suggests that ATM and nibrin may function in the same biochemical pathway. Here we demonstrate that nibrin is phosphorylated within one hour of treatment of cells with IR. This response is abrogated in A-T cells that either do not express ATM protein or express near full-length mutant protein. We also show that ATM physically interacts with and phosphorylates nibrin on serine 343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association as revealed by radiation-induced foci formation. Our data provide a biochemical explanation for the similarity in phenotype between A-T and NBS.
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PMID:ATM-dependent phosphorylation of nibrin in response to radiation exposure. 1080 69

Germline mutations of BRCA1 predispose women to breast and ovarian cancers. BRCA1 contains several functional domains that interact directly or indirectly with a variety of molecules, including tumor suppressors (p53, RB, BRCA2 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) and others. Mounting evidence indicates that these physical associations are not artifacts; rather, BRCA1 is likely to serve as an important central component in multiple biological pathways that regulate cell-cycle progression, centrosome duplication, DNA damage repair, cell growth and apoptosis, and transcriptional activation and repression. This review examines our understanding of the significance of the interactions between BRCA1 and other proteins, through which BRCA1 maintains genome integrity and represses tumor formation. Published 2000 John Wiley & Sons, Inc.
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PMID:Roles of BRCA1 and its interacting proteins. 1091 3

Mutations of the ATM and NBS1 genes are responsible for the inherited Ataxia-Telangiectasia and Nijmegen Breakage Syndrome, both of which are associated with a predisposition to cancer. A related syndrome, the Ataxia-Telangiectasia-like disorder, is due to mutations of the MRE11 gene. However, the role of this gene in cancer development has not been established. Here we describe an often homozygous mutation of the poly(T)11 repeat within human MRE11 intron 4 that leads to aberrant splicing, impairment of wild-type MRE11 expression and generation of a truncated protein. This mutation is present in mismatch repair-deficient, but not proficient, colorectal cancer cell lines and primary tumours and is associated with reduced expression of the MRE11--NBS1--RAD50 complex, an impaired S-phase checkpoint and abrogation of MRE11 and NBS1 ionizing radiation-induced nuclear foci. Our findings identify MRE11 as a novel and major target for inactivation in mismatch repair-defective cells and suggest its impairment may contribute to the development of colorectal cancer.
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PMID:Human MRE11 is inactivated in mismatch repair-deficient cancers. 1185 Mar 99

NFBD1/KIAA0170 is a nuclear factor with an N-terminal FHA (forkhead-associated) domain and a tandem repeat of BRCT (breast cancer susceptibility gene-1 C terminus) domains, both of which are present in a number of proteins involved in DNA repair and/or DNA damage signaling pathways. We have investigated the association of NFBD1 with DNA damage responses. We found that the NFBD1 transcript is abundant in the testis relative to other tissues. NFBD1 is a chromatin-associated protein and is modified in G(2)/M phase or after DNA damage. NFBD1 phosphorylation in response to ionizing radiation (IR) was ATM-dependent. NFBD1 exhibited diffuse nuclear staining in the majority of untreated cells analyzed by indirect immunofluorescence and formed discrete nuclear foci after exposure to IR, UV radiation, and hydroxyurea treatment. IR induced NFBD1 foci within 1 min. The foci colocalized with gamma-H2AX foci, which have been previously shown to localize at sites of DNA double-strand breaks. IR-induced NFBD1 foci also colocalized with 53BP1 and MRE11/RAD50 foci. Taken together, these results suggest that NFBD1 is a mediator of DNA damage-dependent signaling.
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PMID:NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. 1249 69

Alterations of the NBS1 gene are responsible for Nijmegen breakage syndrome (NBS), which is characterized by chromosomal instability, radiosensitivity, and cancer predisposition. NBS1 protein (Nibrin) is part of a molecular complex (NBS1- MRE11A-RAD50) that is functionally involved in DNA double-strand-break repair. Defects in recombination or in repair mechanisms at the level of DNA breakage can lead to chromosomal aberrations, genetic instability, as well as cancer predisposition syndromes (i.e., NBS, ataxia-telangiectasia, Bloom syndrome). In this study, we examined 20 cancer cell lines to evaluate the potential involvement of NBS1 in tumoral pathogenesis. Three different mutations, generating truncated or aberrant NBS1 transcripts, were identified at the level of NBS1 mRNA. In addition, two shorter NBS1 protein variants were detected in two cell lines. These data suggest a possible involvement of NBS1 in tumor development.
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PMID:New mutations and protein variants of NBS1 are identified in cancer cell lines. 1250 48

Telomeres, functional complexes that protect eukaryotic chromosome ends, participate in the regulation of cell proliferation and could play a role in the stabilization of genomic regions in response to genotoxic stress. Their significance in human pathology becomes evident in several diseases sharing genomic instability as a common trait, in which alterations of the telomere metabolism have been demonstrated. Many of them are also associated with hypersensitivity to ionizing radiation and cancer susceptibility. Besides the specific proteins belonging to the telomeric complex, other proteins involved in the DNA repair machinery, such as ATM, BRCA1, BRCA2, PARP/tankyrase system, DNA-PK and RAD50-MRE11-NBS1 complexes, are closely related with the telomere. This suggests that the telomere sequesters DNA repair proteins for its own structure maintenance, which could also be released toward damaged sites in the genomic DNA. This communication describes essential aspects of telomere structure and function and their links with homologous recombination, non-homologous end-joining (NHEJ), V(D)J system and mismatch-repair (MMR). Several pathological conditions exhibiting alterations in some of these mechanisms are also considered. The cell response to ionizing radiation and its relationship with the telomeric metabolism is particularly taken into account as a model for studying genotoxicity.
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PMID:[Telomeres and genomic damage repair. Their implication in human pathology]. 1253 99

MRE11, RAD50 and NBS1 form a highly conserved protein complex (the MRE11 complex) that is involved in the detection, signalling and repair of DNA damage. We identify MDC1 (KIAA0170/NFBD1), a protein that contains a forkhead-associated (FHA) domain and two BRCA1 carboxy-terminal (BRCT) domains, as a binding partner for the MRE11 complex. We show that, in response to ionizing radiation, MDC1 is hyperphosphorylated in an ATM-dependent manner, and rapidly relocalizes to nuclear foci that also contain the MRE11 complex, phosphorylated histone H2AX and 53BP1. Downregulation of MDC1 expression by small interfering RNA yields a radio-resistant DNA synthesis (RDS) phenotype and prevents ionizing radiation-induced focus formation by the MRE11 complex. However, downregulation of MDC1 does not abolish the ionizing radiation-induced phosphorylation of NBS1, CHK2 and SMC1, or the degradation of CDC25A. Furthermore, we show that overexpression of the MDC1 FHA domain interferes with focus formation by MDC1 itself and by the MRE11 complex, and induces an RDS phenotype. These findings reveal that MDC1-mediated focus formation by the MRE11 complex at sites of DNA damage is crucial for the efficient activation of the intra-S-phase checkpoint.
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PMID:MDC1 is required for the intra-S-phase DNA damage checkpoint. 1260 3

Previous work from our laboratory has implicated oxidative DNA damage and genetic instability in the etiology of transforming growth factor-alpha (TGFalpha)/c-myc-associated hepatocarcinogenesis. In contrast, oxidative DNA damage was lower in c-myc single-transgenic mice, consistent with less chromosomal damage and with later and more benign tumor formation. We examined whether defects in the DNA repair pathways contribute to the acceleration of liver cancer in TGFalpha/c-myc mice. A cDNA expression array containing 140 known genes and multiplex RT-PCR were used to compare the basal levels of expression of DNA repair genes at the dysplastic stage. Thirty-five percent (8/23) and 43% (10/23) of DNA repair genes were constitutively up-regulated in 10-week-old TGFalpha/c-myc and c-myc transgenic livers, respectively, compared with wild-type controls. The commonly up-regulated genes were OGG1 and NTH1 of base excision repair; ERCC5, RAD23A, and RAD23B of nucleotide excision repair; and RAD50, RAD52, and RAD54 involved in DNA strand break repair. Additional treatment with a peroxisome proliferator, Wy-14,643, known to increase the level of oxidants in the liver, failed to induce a further increase in the expression level of DNA repair enzymes in TGFalpha/c-myc but not in c-myc or wild-type livers. Moreover, expression of several genes, including Ku80, PMS2, and ATM, was decreased in TGFalpha/c-myc livers, suggesting a fault or inefficient activation of the DNA repair pathway upon induction of oxidative stress. Together, the results show that DNA damage response is attenuated in TGFalpha/c-myc mice, creating a condition that may contribute to acceleration of liver cancer in this model.
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PMID:Dysregulation of DNA repair pathways in a transforming growth factor alpha/c-myc transgenic mouse model of accelerated hepatocarcinogenesis. 1274 74

Phosphorylation of NBS1, the product of the gene mutated in Nijmegen breakage syndrome (NBS), by ataxia telangiectasia mutated (ATM), the product of the gene mutated in ataxia telangiectasia, is required for activation of the S phase checkpoint in response to ionizing radiation (IR). However, NBS1 is also thought to play additional roles in the cellular response to DNA damage. To clarify these additional functions of NBS1, we generated NBS cell lines stably expressing various NBS1 mutants from retroviral vectors. The ATM-dependent activation of CHK2 by IR was defective in NBS cells but was restored by ectopic expression of wild-type NBS1. The defects in ATM-dependent activation of CHK2, S phase checkpoint control, IR-induced nuclear focus formation, and radiation sensitivity apparent in NBS cells were not corrected by expression of NBS1 mutants that lack an intact MRE11 binding domain, suggesting that formation of the NBS1-MRE11-RAD50 complex is required for the corresponding normal phenotypes. Expression of NBS1 proteins with mutated ATM-targeted phosphorylation sites (serines 278 or 343) did not restore S phase checkpoint control but did restore the ability of IR to activate CHK2 and to induce nuclear focus formation and normalized the radiation sensitivity of NBS cells. Expression of NBS1 containing mutations in the forkhead-associated or BRCA1 COOH terminus domains did not correct the defects in radiation sensitivity or nuclear focus formation but did restore S phase checkpoint control in NBS cells. Together, these data demonstrate that multiple functional domains of NBS1 are required for ATM-dependent activation of CHK2, nuclear focus formation, S phase checkpoint control, and cell survival after exposure to IR.
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PMID:Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. 1286 Oct 53


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