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NCI CANCERLIT^® Search: Ataxia Telangiectasia - October 2002

Imprima English

National Cancer Institute^®
Ultima Vez Modificado: 1 de octubre del 2002

Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome.
MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.
Caretaker tumour suppressor genes that defend genome integrity.
Multiple sclerosis in a radiosensitive family with low levels of the ATM protein.
ATM induction insufficiency in a radiosensitive breast-cancer patient.
Gene expression phenotype in heterozygous carriers of ataxia telangiectasia.
[Changes in the radiation-induced apoptotic response in homozygotes and heterozygotes for the ataxia-telangiectasia gene]
Cellular response to DNA damage. Link between p53 and DNA-PK.

Table of Contents

1
UI - 11282395
AU - Harfst E; Cooper S; Neubauer S; Distel L; Grawunder U
TI - Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome.
SO - Mol Immunol 2000 Oct;37(15):915-29
AD - Basel Institute for Immunology, Grenzacherstr. 487, CH-4005, Basel, Switzerland.
The majority of antigen receptor diversity in mammals is generated by V(D)J recombination. During this process DNA double strand breaks are introduced at recombination signals by lymphoid specific RAG1/2 proteins generating blunt ended signal ends and hairpinned coding ends. Rejoining of all DNA ends requires ubiquitously expressed DNA repair proteins, such as Ku70/86 and DNA ligase IV/XRCC4. In addition, the formation of coding joints depends on the function of the scid gene encoding the catalytic subunit of DNA-dependent protein kinase, DNA-PK(CS), that is somehow required for processing of coding end hairpins. Recently, it was shown that purified RAG1/2 proteins can cleave DNA hairpins in vitro, but the same activity was also described for a protein complex of the DNA repair proteins Nbs1/Mre11/Rad50. This leaves the possibility that either protein complex might be involved in coding end processing in V(D)J recombination. We have therefore analyzed V(D)J recombination in cells from patients with Nijmegen breakage syndrome, carrying a mutation in the nbs1 gene. We find that V(D)J recombination frequencies and the quality of signal and coding joining are comparable to wild-type controls, as analyzed by a cellular V(D)J recombination assay. In addition, we did not detect significant differences in CDR3 sequences of endogenous Ig lambdaL and kappaL chain gene loci cloned from peripheral blood lymphocytes of an NBS patient and of healthy individuals. These findings suggest that the Nbs1/Mre11/Rad50 complex is not involved in coding end processing of V(D)J recombination.

2
UI - 10367890
AU - Mills KD; Sinclair DA; Guarente L
TI - MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.
SO - Cell 1999 May 28;97(5):609-20
AD - Massachusetts Institute of Technology, Department of Biology, Cambridge 02139, USA.
The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair.

3
UI - 11927276
AU - Levitt NC; Hickson ID
TI - Caretaker tumour suppressor genes that defend genome integrity.
SO - Trends Mol Med 2002 Apr;8(4):179-86
AD - Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK OX3 9DS.
Cancers arise as a result of genetic changes that impact upon cell proliferation through promoting cell division and/or inhibiting cell death. Tumour suppressor (TS) genes are the targets for many of these genetic changes. In general, both alleles of TS genes must be disrupted to observe a phenotypic effect. Broadly speaking, there are two types of TS gene: 'gatekeepers' and 'caretakers'. In contrast to gatekeepers, caretaker genes do not directly regulate proliferation, but act to prevent genomic instability. Thus, mutation of caretaker genes leads to accelerated conversion of a normal cell to a neoplastic cell. Many caretaker genes are required for the maintenance of genome integrity. This review focuses on those caretaker genes that play a role, directly or indirectly, in the repair of DNA strand breaks by the homologous recombination pathway, and that are associated with cancer-prone clinical syndromes, in particular ataxia telangiectasia, hereditary breast cancer, Bloom's syndrome and Werner's syndrome.

4
UI - 12196235
AU - Clarke RA; Fang ZM; Lee CS; Sarris M; Murrell D; Kearsley JH
TI - Multiple sclerosis in a radiosensitive family with low levels of the ATM protein.
SO - Australas Radiol 2002 Sep;46(3):267-74
AD - Division of Cancer Services, The St George Hospital, University of New South Wales, Australia. R.Clarke@unsw.edu.au
Multiple sclerosis (MS) is a chronic neurological disease of the central nervous system (CNS) characterized by demyelination associated with progressive disability. The mechanisms underlying the pathogenesis of MS remain a mystery. The highly pleiotropic syndrome known as ataxia telangiectasia (A-T) overlaps with MS in that it also presents with demyelination in the CNS. Whether demyelination in MS or in A-T is initiated through neuronal degeneration or immune dysfunction is not yet known. However, unlike MS, the underlying cause of A-T is known to result from mutations in the A-T gene (ATM) that often result in the complete loss of ATM protein and loss/gain of function. ATM is implicated in neurological degeneration, particularly in the cerebellum, cellular apoptosis, immunodeficiency, double stranded deoxyribonucleic acid (DNA) rejoining, VDJ antibody recombination, tumour suppression, particularly T-lymphoid malignancies, signal transduction, cell-cycle control and cellular radiohypersensitivity. In this study, we describe a case of MS in a family with cellular radiosensitivity and abnormally low postinduction levels of the ATM protein. Defective DNA repair/rejoining may impact on autoimmunity.

5
UI - 12196249
AU - Clarke RA; Fang ZH; Marr PJ; Lee CS; Kearsley JH; Papadatos G
TI - ATM induction insufficiency in a radiosensitive breast-cancer patient.
SO - Australas Radiol 2002 Sep;46(3):329-35
AD - Molecular Genetics Laboratories, Cancer Care Center, Division of Cancer Services, The St George Hospital and University of New South Wales, Australia. r.clarke@unsw.edu.au
The ataxia telangiectasia (A-T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology.

6
UI - 12226795
AU - Watts JA; Morley M; Burdick JT; Fiori JL; Ewens WJ; Spielman RS; Cheung
TI - VG Gene expression phenotype in heterozygous carriers of ataxia telangiectasia.
SO - Am J Hum Genet 2002 Oct;71(4):791-800
AD - Department of Pediatrics, University of Pennsylvania, Philadelphia 19104, USA.
The defining characteristic of recessive diseases is the absence of a phenotype in the heterozygous carriers. Nonetheless, subtle manifestations may be detectable by new methods, such as expression profiling. Ataxia telangiectasia (AT) is a typical recessive disease, and individual carriers cannot be reliably identified. As a group, however, carriers of an AT disease allele have been reported to have a phenotype that distinguishes them from normal control individuals: increased radiosensitivity and risk of cancer. We show here that the phenotype is also detectable, in lymphoblastoid cells from AT carriers, as changes in expression level of many genes. The differences are manifested both in baseline expression levels and in response to ionizing radiation. Our findings show that carriers of a recessive disease may have an "expression phenotype." In the particular case of AT, this suggests a new approach to the identification of carriers and enhances understanding of their increased cancer risk. More generally, we demonstrate that genomic technologies offer the opportunity to identify and study unaffected carriers, who are hundreds of times more common than affected patients.

7
UI - 7882143
AU - Duchaud E; Ridet A; Delic Y; Cundari E; Moustacchi E; Rosselli F
TI - [Changes in the radiation-induced apoptotic response in homozygotes and heterozygotes for the ataxia-telangiectasia gene]
SO - C R Acad Sci III 1994 Nov;317(11):983-9
AD - URA 1292 du CNRS, Institut Curie-Biologie, Paris, France.
Ataxia-telangiectasia is a progressive recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation hypersensitivity and increased predisposition to cancer. Impaired induction of the tumor suppressor protein p53 after gamma-irradiation was recently reported. All together these characteristics may be compatible with an inability to correctly regulate the apoptotic pathway of cell death in this syndrome. We show here that lymphocyte cultures from AT patients are characterized by a 3 times more elevated spontaneous level of apoptotic cells compared to normal ones. In spite of this, 24 h after exposure to gamma-irradiation (5 to 10 Gy), AT lymphocytes show a dramatically reduced capacity to undergo apoptosis compared to normal cells. We obtained similar results on EBV-transformed lymphoblasts. Interestingly, lymphoblasts from obligate heterozygous for the AT mutation(s) show the same features as AT lymphoblasts, i.e. an elevated frequency of spontaneous and a reduced level of radio-induced apoptotic figures in comparison to normal cultured cells. In conclusion, we show here, for the first time, that mutation(s) in AT gene(s) results in an impaired ability to correctly regulate the apoptotic pathway of cell death.

8
UI - 10196661
AU - Salles-Passador I; Fotedar A; Fotedar R
TI - Cellular response to DNA damage. Link between p53 and DNA-PK.
SO - C R Acad Sci III 1999 Feb-Mar;322(2-3):113-20
AD - Institut de biologie structurale J.-P.-Ebel, Grenoble, France.
Cells which lack DNA-activated protein kinase (DNA-PK) are very susceptible to ionizing radiation and display an inability to repair double strand DNA breaks. DNA-PK is a member of a protein kinase family that includes ATR and ATM which have strong homology in their carboxy-terminal kinase domain with PL-3 kinase. ATM has been proposed to act upstream of p53 in cellular response to ionizing radiation. DNA-PK may similarly interact with p53 in cellular growth control and in mediation of the response to ionizing radiation.

The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.

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