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)

Chromosomal instability can occur when the DNA damage response and repair process fails, resulting in syndromes characterized by growth abnormalities, hematopoietic defects, mutagen sensitivity, and cancer predisposition. Mutations in ATM, NBS1, MRE11, BLM, WRN, and FANCD2 are responsible for ataxia telangiectasia (AT), Nijmegen breakage syndrome, AT-like disorder, Bloom and Werner syndrome, and Fanconi anemia group D2, respectively. This diverse group of disorders is thought to be linked through protein interactions with the breast cancer tumor susceptibility gene product, BRCA1. BRCA1 forms a multi-subunit protein complex referred to as the BRCA1-associated genome surveillance complex (BASC), which includes DNA damage repair proteins such as MSH2-MSH6 and MLH1, as well as ATM, NBS1, MRE11, and BLM. Although still controversial, this finding suggests similarities in the pathogenesis of the human chromosome breakage syndromes and a complementary role for each protein in DNA structure surveillance or damage repair.
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PMID:Chromosomal breakage syndromes and the BRCA1 genome surveillance complex. 1173 19

Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers. FA cells are hypersensitive to mitomycin C (MMC), while AT cells are hypersensitive to ionizing radiation (IR). Here, we identify the Fanconi anemia protein, FANCD2, as a link between the FA and ATM damage response pathways. ATM phosphorylates FANCD2 on serine 222 in vitro. This site is also phosphorylated in vivo in an ATM-dependent manner following IR. Phosphorylation of FANCD2 is required for activation of an S phase checkpoint. The ATM-dependent phosphorylation of FANCD2 on S222 and the FA pathway-dependent monoubiquitination of FANCD2 on K561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 results in both MMC and IR hypersensitivity.
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PMID:Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. 1208 3

The accumulation of DNA repair proteins at the sites of DNA damage can be visualized in mutagenized cells at the single cell level as discrete nuclear foci by immunofluorescent staining. Formation of nuclear foci in irradiated human fibroblasts, as detected by antibodies directed against the DNA repair protein MRE11, is significantly disturbed by the presence of the viral oncogene, SV40 large T-antigen. The attenuation of foci formation was found in both T-antigen immortalized cells and in cells transiently expressing T-antigen, indicating that it is not attributable to secondary mutations but to T-antigen expression itself. ATM-mediated nibrin phosphorylation was not altered, thus the disturbance of MRE11 foci formation by T-antigen is independent of this event. The decrease in MRE11 foci was particularly pronounced in T-antigen immortalized cells from the Fanconi anaemia complementation group FA-D2. FA-D2 cells produce essentially no MRE11 DNA repair foci after ionizing irradiation and have a significantly increased cellular radiosensitivity at low radiation doses. The gene mutated in FA-D2 cells, FANCD2, codes for a protein which also locates to nuclear foci and may, therefore, be involved in MRE11 foci formation, at least in T-antigen immortalized cells. This finding possibly links Fanconi anaemia proteins to the frequently reported increased sensitivity of Fanconi anaemia cells to transformation by SV40. From a practical stand point these findings are particularly relevant to the many studies on DNA repair which exploit the advantages of SV40 immortalized cell lines. The interference of T-antigen with DNA repair processes, as demonstrated here, should be borne in mind when interpreting such studies.
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PMID:SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11. 1211 65

Fanconi anaemia (FA) is a rare autosomal recessive disease characterized by increased spontaneous and DNA crosslinker-induced chromosome instability, progressive pancytopenia and cancer susceptibility. An increasing number of genes are involved in FA, including the breast cancer susceptibility gene BRCA2. Five of the FA proteins (FANCA, FANCC, FANCE, FANCF and FANCG) assemble in a complex that is required for FANCD2 activation in response to DNA crosslinks. Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci. FANCD2 is independently phosphorylated by ATM (the protein whose gene is mutated in ataxia telangiectasia) in response to ionizing radiation. In addition, the FA proteins are interconnected with other nuclear and cytoplasmic factors all related to cellular responses to carcinogenic stress and to caretaker and gatekeeper functions. In this review, the most recently published data on the molecular biology of the FA pathway and its molecular crosstalk with ATM, BRCA1 and BRCA2, proteins involved in xenobiotic and reactive oxygen species metabolism, apoptosis, cell cycle control and telomere stability, are summarized. The currently available data indicate that FA is a central node in a complex nuclear and cytoplasmic network of tumour suppressor and genome stability pathways fully committed to prevent cancer.
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PMID:The Fanconi anaemia genome stability and tumour suppressor network. 1243 50

Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) are autosomal recessive chromosome instability syndromes with distinct clinical phenotypes. Cells from individuals affected with FA are hypersensitive to mitomycin C (MMC), and cells from those with NBS are hypersensitive to ionizing radiation. Here we report that both NBS cell lines and individuals with NBS are hypersensitive to MMC, indicating that there may be functional linkage between FA and NBS. In wild-type cells, MMC activates the colocalization of the FA subtype D2 protein (FANCD2) and NBS1 protein in subnuclear foci. Ionizing radiation activates the ataxia telangiectasia kinase (ATM)-dependent and NBS1-dependent phosphorylation of FANCD2, resulting in an S-phase checkpoint. NBS1 and FANCD2 therefore cooperate in two distinct cellular functions, one involved in the DNA crosslink response and one involved in the S-phase checkpoint response.
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PMID:Interaction of FANCD2 and NBS1 in the DNA damage response. 1244 95

The present report deals with the functional relationships among protein complexes which, when mutated, are responsible for four human syndromes displaying cancer proneness, and whose cells are deficient in DNA double-strand break (DSB) repair. In some of them, the cells are also unable to activate the proper checkpoint, while in the others an unduly override of the checkpoint-induced arrest occurs. As a consequence, all these patients display genome instability. In ataxia-telangiectasia, the mutated protein (ATM) is a kinase, which acts as a transducer of DNA damage signalling. The defective protein in the ataxia-telangiectasia-like disorder is a DNase (the Mre11 nuclease) that in vivo produces single-strand tails at both sides of DSBs. Mre11 is always present with the Rad50 ATPase in a protein machine: the nuclease complex. In mammals, this complex also contains nibrin, the protein mutated in the Nijmegen syndrome. Nibrin confers new abilities to the nuclease complex, and can also bind to BRCA1 (one of the two proteins mutated in familial breast cancer). BRCA1 has a central motif that binds with high affinity to cruciform DNA, a structure present in places where the DNA loops are anchored to the chromosomal axis or scaffold. The BRCA1 x cruciform DNA complex should be released to allow the nuclease complex to work in DNA recombinational repair of DSBs. BRCA1 also acts as a scaffold for the assembly of ATPases such as Rad51, responsible for the somatic homologous recombination. Loss of the BRCA1 gene prevents cell survival after exposure to cross-linkers. The BRCA1-RING domain is an E3-ubiquitin ligase. It can mono-ubiquitinate the FANCD2 protein, mutated in one of the Fanconi anemia complementation groups, to regulate it. Finally, during DNA replication, the nuclease complex and its activating ATM kinase are integrated in the BRCA1-associated surveillance complex (BASC) that contains, among others, enzymes required for mismatch excision repair. In short, the proteins missing in these syndromes have in common their BRCA1-mediated assembly into multimeric machines responsible for the surveillance of DNA replication, DSB recombinational repair, and the removal of DNA cross-links.
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PMID:Human syndromes with genomic instability and multiprotein machines that repair DNA double-strand breaks. 1250 2

Fanconi anaemia (FA) is a rare disease characterized by chromosome instability and cancer susceptibility. With the exception of FANCD2, none of the Fanconi anaemia genes are conserved in evolution, limiting the study of the Fanconi anaemia pathway in genetically tractable models. Here we report the cloning and sequencing of a Drosophila full length cDNA homologous to human FANCD2 (dmFANCD2) as a first step in using Drosophila in Fanconi anaemia research. dmFANCD2 is composed of 14 exons coding for a protein of 1478 aminoacids. Southern blot and in situ hybridization analysis indicated that dmFANCD2 is present at single copy in the Drosophila genome and maps at the chromosomal band 92-F3. Sequence and structural biocomputational analysis indicated that, although the aminoacidic sequence, and specially the N-terminus region, is not highly conserved between humans and flies (23% identity and 43% similarity), both proteins are of the same size, globular and compact, with several transmembrane helixes and related to nuclear membrane proteins. Interestingly, the human ATM phosphorylation site at S222 and the complex-dependent monoubiquitination site at K561 are highly conserved in Drosophila at positions S267 and K595, respectively. The same is true for other putative ATM sites and their aminoacidic environment and for two out of three aminoacid mutations associated with human pathology. These results suggest that the key FANCD2 features have been conserved during over 500 million years of divergent evolution, highlighting their biological importance.
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PMID:Molecular cloning of the Drosophila Fanconi anaemia gene FANCD2 cDNA. 1276 53

We provide an overview of the functional interrelationship between genes and proteins related to DNA repair by homologous recombination and cell cycle regulation in relation to the progression and therapy resistance of human tumours. To ensure the high-fidelity transmission of genetic information from one generation to the next, cells have evolved mechanisms to monitor genome integrity. Upon DNA damage, cells initiate complex response pathways including cell cycle arrest, activation of genes and gene products involved in DNA repair, and under some circumstances, the triggering of programmed cell death. Deregulation of this co-ordinated response leads to genetic instability and is fundamental to the aetiology of human cancer. Homologous recombination involved in DNA repair is induced by environmental damage as well as misreplication during the normal cell cycle. However, when not regulated properly, it can result in the loss of heterozygocity or genetic rearrangements, central to the process of carcinogenesis. The central step of homologous recombination is the DNA strand exchange reaction catalysed by the eukaryotic Rad51 protein. Here, we describe the recent progress in our understanding of how Rad51 is involved in the signalling and repair of DNA damage and how tumour suppressors, such as p53, ATM, BRCA1, BRCA2, BLM and FANCD2 are linked to Rad51-dependent pathways. An increased knowledge of the role of Rad51 in DNA repair by homologous recombination and its effects on cell cycle progression, tumour development and tumour resistance may provide opportunities for identifying improved diagnostic markers and developing more effective treatments for cancer.
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PMID:Homologous recombination and cell cycle checkpoints: Rad51 in tumour progression and therapy resistance. 1459 70

The genetic syndrome Fanconi anemia (FA) is characterized by aplastic anemia, cancer predisposition and hypersensitivity to DNA interstrand crosslinks (ICLs). FA proteins (FANCs) are thought to work in pathway(s) essential for dealing with crosslinked DNA. FANCs interact with other proteins involved in both DNA repair and S-phase checkpoint such as BRCA1, ATM and the RAD50/MRE11/NBS1 (RMN) complex. We deciphered the previously undefined pathway(s) leading to the ICLs-induced S-phase checkpoint and the role of FANCs in this process. We found that ICLs activate a branched pathway downstream of the ATR kinase: one branch depending on CHK1 activity and the other on the FANCs-RMN complex. The transient slow-down of DNA synthesis was abolished in cells lacking ATR, whereas CHK1-siRNA-treated cells, NBS1 or FA cells showed partial S-phase arrest. CHK1 RNAi in NBS1 or FA cells abolished the S-phase checkpoint, suggesting that CHK1 and FANCs/NBS1 proteins work on parallel pathways. Furthermore, we found that ICLs trigger ATR-dependent FANCD2 phosphorylation and FANCD2/ATR colocalization. This study demonstrates a novel relationship between the FA pathway(s) and the ATR kinase.
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PMID:The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. 1498 23

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by chromosome instability and cancer predisposition. At least 11 complementation groups for FA have been identified, and eight FA genes have been cloned. Interestingly, the eight known FA proteins cooperate in a common pathway leading to the interaction of monoubiquitinated FANCD2 and BRCA2 in damaged chromatin. Disruption of this pathway results in the clinical and cellular abnormalities common to all FA subtypes. This review will examine the interaction of the cloned FA proteins with each other and with other DNA damage response proteins (i.e., ATM, ATR, and NBS1). Also, somatic (acquired) disruption of the FA pathway in human tumors appears to account for their chromosome instability and crosslinker hypersensitivity.
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PMID:The interplay of Fanconi anemia proteins in the DNA damage response. 1527 94


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