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NCI CANCERLIT^® Search: Ataxia Telangiectasia - July 2002

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

[Life without DNA repair]
DNA-PK and ATM are required for radiation-enhanced integration.
Early diagnosis of ataxia-telangiectasia using radiosensitivity testing.
Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.
ATM: from phenotype to functional genomics--and back.
Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest.
Positional cloning of the gene for Nijmegen breakage syndrome.
[ATM and nibrin, partner proteins, associated with or independent of DNA repair?]
Radiation, DNA damage and cancer.
Many faces of ATM: eighth international workshop on ataxia-telangiectasia.
[Genes and cancer. NBS1 (Nijmegen breakage syndrome). Repair gene]
The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.
ATM-dependent phosphorylation of nibrin in response to radiation exposure.
Cancer. New link in a web of human genes.
Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.
ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response.
Convergence of DNA repair and cell-cycle checkpoint control.
Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1.
Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome.
Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34.
Checkpoints: it takes more than time to heal some wounds.
A novel mutation and novel features in Nijmegen breakage syndrome.
Complementation of chromosomal aberrations in AT/NBS hybrids: inadequacy of RDS as an endpoint in complementation studies with immortal NBS
Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome.
Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation.
Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair.
Alternative end joining during switch recombination in patients with ataxia-telangiectasia.
Re: Dominant negative ATM mutations in breast cancer families.
TEL1 from Saccharomyces cerevisiae suppresses chromosome aberrations induced by ionizing radiation in ataxia-telangiectasia cells without

1
UI - 12013614
AU - Klungland A
TI - [Life without DNA repair]
SO - Tidsskr Nor Laegeforen 2001 Jan 10;121(1):41-9
AD - Seksjon for molekylaerbiologi Mikrobiologisk Institutt Rikshospitalet 0027 Oslo. arne.klungland@labmed.uio.no
BACKGROUND: Faithful maintenance of the genomic information is crucial for the survival of a species. Consequently, DNA repair processes must have evolved early during evolution. DNA damage left unrepaired might cause mutations leading to cell death, increased cancer incidence and severe syndromes. MATERIAL AND METHODS: In 1968, for the first time a link was found between a human syndrome, xeroderma pigmentosum, and a defect in the machinery for DNA repair. These patients develop skin cancer at an early age if not completely protected against sunlight. More recently, several other DNA repair syndromes with cancer predisposition and premature aging have been identified. RESULTS: A number of DNA repair genes causing such defects have now been cloned and characterised. These genes represent different DNA repair pathways and some of them are involved in the coupling between DNA repair and DNA transcription. INTERPRETATION: It is now possible to produce mice models with defects identical to those identified in humans. During the last 5 years, more than 100 mice models with DNA repair deficiency have been produced. Further characterisation of such mice will provide a unique opportunity for understanding the clinical picture caused by altered DNA repair capacity, and also elucidate the complex interaction of different DNA repair genes.

3
UI - 12072877
AU - Sun X; Becker-Catania SG; Chun HH; Hwang MJ; Huo Y; Wang Z; Mitui M;
TI - Sanal O; Chessa L; Crandall B; Gatti RA Early diagnosis of ataxia-telangiectasia using radiosensitivity testing.
SO - J Pediatr 2002 Jun;140(6):724-31
AD - Department of Pathology, UCLA School of Medicine, Los Angeles, California 90095-1732, USA.
OBJECTIVES: To utilize radiosensitivity testing to improve early diagnosis of patients with ataxia-telangiectasia (A-T). STUDY DESIGN: We established normal ranges for the colony survival assay (CSA) by testing cells from 104 patients with typical A-T, 29 phenotypic normal patients, and 19 A-T heterozygotes. We also analyzed 61 samples from patients suspected of having A-T and 25 patients with related disorders to compare the CSA with other criteria in the diagnosis of A-T. RESULTS: When cells were irradiated with 1.0 Gy, the mean survival fraction (microSF +/- 1 SD) for patients with A-T was 13.1% +/- 7.2% compared with 50.1% +/- 13.5% for healthy control patients. These data served to define a diagnostic range for the CSA (ie, <21%), a normal range (>36%), and a nondiagnostic intermediate range of 21% to 36%. The mutations of patients with A-T with intermediate radiosensitivity tended to cluster around the functional domains of the ATM gene. CONCLUSIONS: The CSA is a useful adjunctive test for confirming an early clinical diagnosis of A-T. However, CSA is also abnormal in other chromosomal instability and immunodeficiency disorders.

4
UI - 12086603
AU - Taniguchi T; Garcia-Higuera I; Xu B; Andreassen PR; Gregory RC; Kim ST;
TI - Lane WS; Kastan MB; D'Andrea AD Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways.
SO - Cell 2002 May 17;109(4):459-72
AD - Department of Pediatric Oncology, Dana-Farber Cancer Institute and Department of Pediatrics, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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.

5
UI - 11859564
AU - Shiloh Y
TI - ATM: from phenotype to functional genomics--and back.
SO - Ernst Schering Res Found Workshop 2002;(36):51-70

6
UI - 12082606
AU - Girard PM; Riballo E; Begg AC; Waugh A; Jeggo PA
TI - Nbs1 promotes ATM dependent phosphorylation events including those required for G1/S arrest.
SO - Oncogene 2002 Jun 20;21(27):4191-9
AD - MRC Cell Mutation Unit, University of Sussex, Brighton, East Sussex, BN1 9RR, UK.
Cell lines from Nijmegen Breakage Syndrome (NBS) and ataxia telangiectasia (A-T) patients show defective S phase checkpoint arrest. In contrast, only A-T but not NBS cells are significantly defective in radiation-induced G1/S arrest. Phosphorylation of some ATM substrates has been shown to occur in NBS cells. It has, therefore, been concluded that Nbs1 checkpoint function is S phase specific. Here, we have compared NBS with A-T cell lines (AT-5762ins137) that express a low level of normal ATM protein to evaluate the impact of residual Nbs1 function in NBS cells. The radiation-induced cell cycle response of these NBS and 'leaky' A-T cells is almost identical; normal G2/M arrest after 2 Gy, intermediate G1/S arrest depending on the dose and an A-T-like S phase checkpoint defect. Thus, the checkpoint assays differ in their sensitivity to low ATM activity. Radiation-induced phosphorylation of the ATM-dependent substrates Chk2, RPAp34 and p53-Ser15 are similarly impaired in AT-5762ins137 and NBS cells in a dose dependent manner. In contrast, NBS cells show normal ability to activate ATM kinase following irradiation in vitro and in vivo. We propose that Nbs1 facilitates ATM-dependent phosphorylation of multiple downstream substrates, including those required for G1/S arrest.

7
UI - 9620777
AU - Matsuura S; Tauchi H; Nakamura A; Kondo N; Sakamoto S; Endo S; Smeets D;
TI - Solder B; Belohradsky BH; Der Kaloustian VM; Oshimura M; Isomura M; Nakamura Y; Komatsu K Positional cloning of the gene for Nijmegen breakage syndrome.
SO - Nat Genet 1998 Jun;19(2):179-81
AD - Department of Radiation Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies and linkage analysis. Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation.

8
UI - 9817056
AU - Bay JO
TI - [ATM and nibrin, partner proteins, associated with or independent of DNA repair?]
SO - Bull Cancer 1998 Sep;85(9):743-4

9
UI - 10203748
AU - Hall J; Angele S
TI - Radiation, DNA damage and cancer.
SO - Mol Med Today 1999 Apr;5(4):157-64
AD - Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France. hall@iarc.fr
The characterization of the rare, radiation-sensitive and cancer-prone syndromes, ataxia telangiectasia and Nijmegen breakage syndrome, has demonstrated that genetic predisposition increases the risk of developing cancer after exposure to ionizing radiation (IR). Molecular analyses of these disorders provide valuable insights into the normal function of these two gene products in the cellular response to IR-induced DNA damage. Their contribution to a cellular radiosensitive phenotype and their role in sporadic cancers can now be fully assessed. For example, the gene ataxia telangiectasia mutated (ATM) has recently been shown to be a tumour suppressor gene in T-cell prolymphocytic leukaemia, and there is increasing evidence that individuals with one mutated ATM or Nijmegen breakage syndrome (NBS1) allele have an increased predisposition to cancer.

10
UI - 10528155
AU - Halazonetis TD; Shiloh Y
TI - Many faces of ATM: eighth international workshop on ataxia-telangiectasia.
SO - Biochim Biophys Acta 1999 Oct 29;1424(2-3):R45-55
AD - Wistar Institute, Department of Pathology of the University of Pennsylvania, Philadelphia, PA, USA. halazonetis@wistar.upenn.edu

11
UI - 10610129
AU - Soussi T
TI - [Genes and cancer. NBS1 (Nijmegen breakage syndrome). Repair gene]
SO - Bull Cancer 1999 Oct;86(10):803-4
AD - Institut Curie, Paris.

12
UI - 10612394
AU - Stewart GS; Maser RS; Stankovic T; Bressan DA; Kaplan MI; Jaspers NG;
TI - Raams A; Byrd PJ; Petrini JH; Taylor AM The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder.
SO - Cell 1999 Dec 10;99(6):577-87
AD - The University of Birmingham CRC Institute for Cancer Studies, The Medical School Edgbaston, United Kingdom.
We show that hypomorphic mutations in hMRE11, but not in ATM, are present in certain individuals with an ataxia-telangiectasia-like disorder (ATLD). The cellular features resulting from these hMRE11 mutations are similar to those seen in A-T as well as NBS and include hypersensitivity to ionizing radiation, radioresistant DNA synthesis, and abrogation of ATM-dependent events, such as the activation of Jun kinase following exposure to gamma irradiation. Although the mutant hMre11 proteins retain some ability to interact with hRad50 and Nbs1, formation of ionizing radiation-induced hMre11 and Nbs1 foci was absent in hMRE11 mutant cells. These data demonstrate that ATM and the hMre11/hRad50/Nbs1 protein complex act in the same DNA damage response pathway and link hMre11 to the complex pathology of A-T.

13
UI - 10802669
AU - Gatei M; Young D; Cerosaletti KM; Desai-Mehta A; Spring K; Kozlov S;
TI - Lavin MF; Gatti RA; Concannon P; Khanna K ATM-dependent phosphorylation of nibrin in response to radiation exposure.
SO - Nat Genet 2000 May;25(1):115-9
AD - The Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane, Queensland, Australia.
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.

14
UI - 10839519
AU - Wang JY
TI - Cancer. New link in a web of human genes.
SO - Nature 2000 May 25;405(6785):404-5

15
UI - 10839544
AU - Zhao S; Weng YC; Yuan SS; Lin YT; Hsu HC; Lin SC; Gerbino E; Song MH;
TI - Zdzienicka MZ; Gatti RA; Shay JW; Ziv Y; Shiloh Y; Lee EY Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products.
SO - Nature 2000 May 25;405(6785):473-7
AD - Department of Molecular Medicine/Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 78245-3207, USA.
Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mrel1. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mrel1/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes.

16
UI - 10839545
AU - Wu X; Ranganathan V; Weisman DS; Heine WF; Ciccone DN; O'Neill TB; Crick
TI - KE; Pierce KA; Lane WS; Rathbun G; Livingston DM; Weaver DT ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response.
SO - Nature 2000 May 25;405(6785):477-82
AD - Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nijmegen breakage syndrome (NBS) is characterized by extreme radiation sensitivity, chromosomal instability and cancer. The phenotypes are similar to those of ataxia telangiectasia mutated (ATM) disease, where there is a deficiency in a protein kinase that is activated by DNA damage, indicating that the Nbs and Atm proteins may participate in common pathways. Here we report that Nbs is specifically phosphorylated in response to gamma-radiation, ultraviolet light and exposure to hydroxyurea. Phosphorylation of Nbs mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, Nbs was phosphorylated on many serine residues, of which S343, S397 and S615 were phosphorylated by Atm in vitro. At least two of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated Atm-dependent phosphorylation. Reconstituting NBS cells with a mutant form of Nbs that cannot be phosphorylated at selected, ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Thus, phosphorylation of Nbs by Atm is critical for certain responses of human cells to DNA damage.

17
UI - 10854333
AU - Eggleston A
TI - Convergence of DNA repair and cell-cycle checkpoint control.
SO - Nat Cell Biol 2000 Jun;2(6):E95

18
UI - 10838806
AU - Tauchi H
TI - Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1.
SO - J Radiat Res (Tokyo) 2000 Mar;41(1):9-17
AD - Department of Radiation Biology, Hiroshima University, Japan. htauchi@hiroshima-u.ac.jp
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, combined immunodeficiency, and a high incidence of lymphoid tumor. Cells from NBS patients show chromosomal instability, hypersensitivity to ionizing radiation and abnormal p53-mediated cell cycle regulation. We cloned the underlying gene for NBS, designated NBS1, by complementation-assisted positional cloning from the candidate region 8q21. Large genomic sequencing, as well as a search using computer programs, provides a powerful approach for identifying the underlying gene for a disease. The NBS1 gene encodes a protein of 754 amino acids that has FHA and BRCT domains which often are conserved in cell-cycle checkpoint proteins. The gene has weak homology to the yeast (Saccharomyces cerevisiae) Xrs2 protein in the N-terminus region. Like yeast Xrs2, the NBS1 protein forms a complex with hRAD50/hMRE11, and the complex is condensed as foci in the nucleus after irradiation, indicative that this triple-complex is a crucial factor in DNA repair. Functional analysis of the NBS1 protein is in progress and it should provide further clues to understanding the repair mechanism of radiation-induced DNA double-strand breaks.

19
UI - 10852373
AU - Kleier S; Herrmann M; Wittwer B; Varon R; Reis A; Horst J
TI - Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome.
SO - Clin Genet 2000 May;57(5):384-7
AD - Institut fur Humangenetik, Westfalische-Wilhelms-Universitat, Munster, Germany.
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder which belongs to the group of inherited chromosomal instability syndromes. The clinical characteristics include severe microcephaly, a dysmorphic facies, and immunodeficiency with predisposition to malignancies. While the cellular characteristics of ataxia teleangiectasia (AT) and NBS are similar, the clinical findings are quite distinct. NBS patients show characteristic microcephaly, which is rare in association with AT and they do not develop ataxia and teleangiectasia. Recently, the gene mutated in NBS has been identified. Here we report a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for AT (MIM 208900) and NBS (MIM 251260), AT was diagnosed. We suggested the diagnosis of NBS because of the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and teleangiectasia. DNA analysis was performed and revealed that the boy is homozygous for the major mutation (657de15) in the NBS1 gene. This finding confirms the diagnosis of NBS in our patient and offers the possibility to perform a most reliable prenatal diagnosis in a further pregnancy.

20
UI - 11022012
AU - Nemeth AH; Bochukova E; Dunne E; Huson SM; Elston J; Hannan MA; Jackson
TI - M; Chapman CJ; Taylor AM Autosomal recessive cerebellar ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome) is linked to chromosome 9q34.
SO - Am J Hum Genet 2000 Nov;67(5):1320-6
AD - Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, United Kingdom. andrea.nemeth@well.ox.ac.uk
Ataxia with oculomotor apraxia (ataxia-telangiectasia-like syndrome [AOA]; MIM 208920) is an autosomal recessive disorder characterized by ataxia, oculomotor apraxia, and choreoathetosis. These neurological features resemble those of ataxia-telangiectasia (AT), but in AOA there are none of the extraneurological features of AT, such as immunodeficiency, neoplasia, chromosomal instability, or sensitivity to ionizing radiation. It is unclear whether these patients have a true disorder of chromosomal instability or a primary neurodegenerative syndrome, and it has not been possible to identify the defective gene in AOA, since the families have been too small for linkage analysis. We have identified a new family with AOA, and we show that the patients have no evidence of chromosomal instability or sensitivity to ionizing radiation, suggesting that AOA in this family is a true primary cerebellar ataxia. We have localized the disease gene, by linkage analysis and homozygosity mapping, to a 15.9-cM interval on chromosome 9q34. This work will ultimately allow the disease gene to be identified and its relevance to other types of autosomal recessive cerebellar ataxias to be determined.

21
UI - 11137027
AU - Rhind N; Russell P
TI - Checkpoints: it takes more than time to heal some wounds.
SO - Curr Biol 2000 Dec 14-28;10(24):R908-11
AD - The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. rhind@scripps.edu
The S-phase DNA damage checkpoint seems to provide a twist on the checkpoint theme. Instead of delaying replication and allowing repair as a consequence, it may activate repair and delay replication as a consequence.

22
UI - 11288710
AU - Maraschio P; Danesino C; Antoccia A; Ricordy R; Tanzarella C; Varon R;
TI - Reis A; Besana D; Guala A; Tiepolo L A novel mutation and novel features in Nijmegen breakage syndrome.
SO - J Med Genet 2001 Feb;38(2):113-7

23
UI - 11267829
AU - Kraakman-van der Zwet M; Overkamp WJ; Jaspers NG; Natarajan AT; Lohman
TI - PH; Zdzienicka MZ Complementation of chromosomal aberrations in AT/NBS hybrids: inadequacy of RDS as an endpoint in complementation studies with immortal NBS cells.
SO - Mutat Res 2001 Apr 4;485(3):177-85
AD - Department of Radiation Genetics and Chemical Mutagenesis - MGC, Wassenaarseweg 72, 2333 AL, Leiden University Medical Center, Leiden, The Netherlands.
Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) are rare autosomal recessive hereditary disorders characterized by radiosensitivity, chromosomal instability, immunodeficiency and proneness to cancer. Although the clinical features of both syndromes are quite distinct, the cellular characteristics are very similar. Cells from both NBS and AT patients are hypersensitive to ionizing radiation (IR), show elevated levels of chromosomal aberrations and display radioresistant DNA synthesis (RDS). The proteins defective in NBS and AT, NBS1 and ATM, respectively, are involved in the same pathway, but their exact relationship is not yet fully understood. Stumm et al. (Am. J. Hum. Genet. 60 (1997) 1246) have reported that hybrids of AT and NBS lymphoblasts were not complemented for chromosomal aberrations. In contrast, we found that X-ray-induced cell killing as well as chromosomal aberrations were complemented in proliferating NBS-1LBI/AT5BIVA hybrids, comparable to that in NBS-1LBI cells after transfer of a single human chromosome 8 providing the NBS1 gene. RDS observed in AT5BIVA cells was reduced in these hybrids to the level of that seen in immortal NBS-1LBI cells. However, the level of DNA synthesis, following ionizing radiation, in SV40 transformed wild-type cell lines was the same as in NBS-1LBI cells. Only primary wild-type cells showed stronger inhibition of DNA synthesis. In summary, these results clearly indicate that RDS cannot be used as an endpoint in functional complementation studies with immortal NBS-1LBI cells, whereas the cytogenetic assay is suitable for complementation studies with immortal AT and NBS cells.

24
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.

25
UI - 11809797
AU - Xu B; Kim ST; Lim DS; Kastan MB
TI - Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation.
SO - Mol Cell Biol 2002 Feb;22(4):1049-59
AD - Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cell cycle checkpoints are among the multiple mechanisms that eukaryotic cells possess to maintain genomic integrity and minimize tumorigenesis. Ionizing irradiation (IR) induces measurable arrests in the G(1), S, and G(2) phases of the mammalian cell cycle, and the ATM (ataxia telangiectasia mutated) protein plays a role in initiating checkpoint pathways in all three of these cell cycle phases. However, cells lacking ATM function exhibit both a defective G(2) checkpoint and a prolonged G(2) arrest after IR, suggesting the existence of different types of G(2) arrest. Two molecularly distinct G(2)/M checkpoints were identified, and the critical importance of the choice of G(2)/M checkpoint assay was demonstrated. The first of these G(2)/M checkpoints occurs early after IR, is very transient, is ATM dependent and dose independent (between 1 and 10 Gy), and represents the failure of cells which had been in G(2) at the time of irradiation to progress into mitosis. Cell cycle assays that can distinguish mitotic cells from G(2) cells must be used to assess this arrest. In contrast, G(2)/M accumulation, typically assessed by propidium iodide staining, begins to be measurable only several hours after IR, is ATM independent, is dose dependent, and represents the accumulation of cells that had been in earlier phases of the cell cycle at the time of exposure to radiation. G(2)/M accumulation after IR is not affected by the early G(2)/M checkpoint and is enhanced in cells lacking the IR-induced S-phase checkpoint, such as those lacking Nbs1 or Brca1 function, because of a prolonged G(2) arrest of cells that had been in S phase at the time of irradiation. Finally, neither the S-phase checkpoint nor the G(2) checkpoints appear to affect survival following irradiation. Thus, two different G(2) arrest mechanisms are present in mammalian cells, and the type of cell cycle checkpoint assay to be used in experimental investigation must be thoughtfully selected.

26
UI - 11889050
AU - Kang J; Bronson RT; Xu Y
TI - Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair.
SO - EMBO J 2002 Mar 15;21(6):1447-55
AD - Section of Molecular Biology, Division of Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
Nijmegen breakage syndrome (NBS) is an autosomal recessive hereditary disease that shares some common defects with ataxia-telangiectasia. The gene product mutated in NBS, named NBS1, is a component of the Mre11 complex that is involved in DNA strand-break repair. To elucidate the physiological roles of NBS1, we disrupted the N-terminal exons of the NBS1 gene in mice. NBS1(m/m) mice are viable, growth retarded and hypersensitive to ionizing radiation (IR). NBS1(m/m) mice exhibit multiple lymphoid developmental defects, and rapidly develop thymic lymphoma. In addition, female NBS1(m/m) mice are sterile due to oogenesis failure. NBS1(m/m) cells are impaired in cellular responses to IR and defective in cellular proliferation. Most systematic and cellular defects identified in NBS1(m/m) mice recapitulate those in NBS patients, and are essentially identical to those observed in Atm(-/-) mice. In contrast to Atm(-/-) mice, spermatogenesis is normal in NBS1(m/m) mice, indicating that distinct roles of ATM have differential requirement for NBS1 activity. Thus, NBS1 and ATM have overlapping and distinct functions in animal development and DNA repair.

27
UI - 11981817
AU - Pan Q; Petit-Frere C; Lahdesmaki A; Gregorek H; Chrzanowska KH;
TI - Hammarstrom L Alternative end joining during switch recombination in patients with ataxia-telangiectasia.
SO - Eur J Immunol 2002 May;32(5):1300-8
AD - Division of Clinical Immunology, IMPI, Karolinska Institutet at Huddinge Hospital, and Center for Biotechnology and Center for Oral Biology, NOVUM, Huddinge, Sweden.
Ataxia-Telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic diseases with similar cellular phenotypes that are caused by mutations in the recently described ATM (encoding ATM) and NBS1 (encoding p95) genes, respectively. Both disorders are accompanied by immunodeficiency in a majority of patients, but the mechanism involved has as yet not been established. We demonstrate that in cells from A-T patients, the switch (S) recombination junctions are aberrant and characterized by a strong dependence on short sequence homologies and devoid of normally occurring mutations around the breakpoint. A low number of S fragments were generated in cells from NBS patients and showed only limited dependence on sequence identity and mutation frequencies were similar to those observed in normal controls. We propose that ATM and p95 are both involved in the final step(s) in class switch recombination with related, but disparate, functional roles. Thus, the general pathway involved in DNA repair also has a major influence on the immunoglobulin isotype switching process.

28
UI - 12072552
AU - Lei H; Pospisilova D; Lindblom A; Vorechovsky I
TI - Re: Dominant negative ATM mutations in breast cancer families.
SO - J Natl Cancer Inst 2002 Jun 19;94(12):951-2; discussion 952

29
UI - 11820740
AU - Cao JP; Meyn MS; Eckardt-Schupp F; Fritz E
TI - TEL1 from Saccharomyces cerevisiae suppresses chromosome aberrations induced by ionizing radiation in ataxia-telangiectasia cells without affecting cell cycle checkpoints.
SO - Radiat Environ Biophys 2001 Dec;40(4):309-15
AD - Soochow University, Suzhou, PR China.
The TEL1 gene from Saccharomyces cerevisiae has been shown to be the closest sequence homologue to ATM, the gene mutated in ataxia-telangiectasia (A-T) patients. Functional homology shared between the ATM and Tell proteins has recently been demonstrated based on heterologous expression of the TEL1 gene in human cells derived from A-T patients. TEL1 expression complemented specific cellular A-T deficiencies, i.e. increased radiation-induced apoptosis, telomere shortening and spontaneous hyperrecombination. The mechanism of cellular A-T complementation by TEL1 appears to be independent of p53-dependent signaling cascades, since the deficiency of A-T cells to properly induce p53 upon ionizing radiation was not corrected by TEL1. We now find that the basic number of chromosome aberrations is increased and the number of radiation-induced chromosome aberrations is suppressed in A-T cells upon TEL1 expression. In cell cycle analyses, we find no changes in basic cell cycle distribution or in radiation-induced cell cycle checkpoints following TEL1 expression. We conclude that the radioprotective function of the Tel1 protein includes suppression of apoptosis and suppression of chromosome aberrations, and that both cellular end-points can be uncoupled from ionizing radiation-induced cell cycle checkpoints.

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