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NCI CANCERLIT^® Search: Ataxia Telangiectasia - April 2002

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

A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity,

[Chromosome instability syndromes]

Recent advances in DNA repair and recombination. A report of the DNA Repair Network meeting, held at City University, London on 19 December

DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene

Cancer predisposition. Ataxia-telangiectasia at the crossroads.

The role of Ataxia telangiectasia and the DNA-dependent protein kinase in the p53-mediated cellular response to ionising radiation.

Cell cycle checkpoints and DNA repair in Nijmegen breakage syndrome.

Essential and perilous: V(D)J recombination and DNA damage checkpoints in lymphocyte precursors.

hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.

Lack of correlation between ATM protein expression and tumour cell radiosensitivity.

Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK

Cellular response to DNA damage. Link between p53 and DNA-PK.

The ATM protein is required for sustained activation of NF-kappaB following DNA damage.

MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.

Many faces of ATM: eighth international workshop on ataxia-telangiectasia.

The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest.

The Mre11 complex and ATM: collaborating to navigate S phase.

Checkpoints: it takes more than time to heal some wounds.

Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.

Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect.

The inherited basis of human radiosensitivity.

Etoposide and adriamycin but not genistein can activate the checkpoint kinase Chk2 independently of ATM/ATR.

Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer.

Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair.

1
UI - 11744712
AU - Kishi S; Lu KP
TI - A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity, and the G(2)/M checkpoint defect of ataxia-telangiectasia cells.
SO - J Biol Chem 2002 Mar 1;277(9):7420-9
AD - Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Cells derived from patients with the human genetic disorder ataxia-telangiectasia (A-T) display many abnormalities, including telomere shortening, premature senescence, and defects in the activation of S phase and G(2)/M checkpoints in response to double-strand DNA breaks induced by ionizing radiation. We have previously demonstrated that one of the ATM substrates is Pin2/TRF1, a telomeric protein that binds the potent telomerase inhibitor PinX1, negatively regulates telomere elongation, and specifically affects mitotic progression. Following DNA damage, ATM phosphorylates Pin2/TRF1 and suppresses its ability to induce abortive mitosis and apoptosis (Kishi, S., Zhou, X. Z., Nakamura, N., Ziv, Y., Khoo, C., Hill, D. E., Shiloh, Y., and Lu, K. P. (2001) J. Biol. Chem. 276, 29282-29291). However, the functional importance of Pin2/TRF1 in mediating ATM-dependent regulation remains to be established. To address this question, we directly inhibited the function of endogenous Pin2/TRF1 in A-T cells by stable expression of two different dominant-negative Pin2/TRF1 mutants and then examined their effects on telomere length and DNA damage response. Both the Pin2/TRF1 mutants increased telomere length in A-T cells, as shown in other cells. Surprisingly, both the Pin2/TRF1 mutants reduced radiosensitivity and complemented the G(2)/M checkpoint defect without inhibiting Cdc2 activity in A-T cells. In contrast, neither of the Pin2/TRF1 mutants corrected the S phase checkpoint defect in the same cells. These results indicate that inhibition of Pin2/TRF1 in A-T cells is able to bypass the requirement for ATM in specifically restoring telomere shortening, the G(2)/M checkpoint defect, and radiosensitivity and demonstrate a critical role for Pin2/TRF1 in the ATM-dependent regulation of telomeres and DNA damage response.

2
UI - 11899541
AU - Seemanova E; Seeman P; Jarolim P
TI - [Chromosome instability syndromes]
SO - Cas Lek Cesk 2002;141(1):16-22
AD - Oddeleni klinicke genetiky Ustavu biologie a lekarske genetiky 2. LF UK, Praha. eva.seemanova@lfmotol.cuni.cz
We refer 55 cases of the chromosomal instability syndromes (SCI), diagnosed in patients of our genetical clinics. Problems of early diagnosis can be documented by a discrepancy between the expected number of patients and their relative advanced age at the time when SCI was ascertained. We have also shown that NBS patients can be diagnosed earlier and the disease sufficiently confirmed on the basis of congenital microcephaly and on the direct detection of 657de15 mutation in NBS1 gene. Genealogical analysis of families with SCI revealed a low risk of prenatal selection of affected homozygotes and high cancer prevalence in relative (in NBS families recognized heterozygotes) at young adult age. Due to severe DNA repair disorder and hyperradiosensitivity of affected homozygotes as well as unaffected heterozygotes, conventional diagnostics and treatment protocols of lymphoreticular malignancies in affected homozygotes are prohibited. The use of Nijmegen treatment protocol improved in our patients dramatically their clinical prognosis, which is documented by 6 NBS patients surviving one or two malignancies. Early diagnose of SCI and information for families and their doctors about consequences of DNA repair disorder and about their hyperradiosensitivity is essential for improving the clinical prognosis of SCI patients.

3
UI - 7596359
AU - Strike P
TI - Recent advances in DNA repair and recombination. A report of the DNA Repair Network meeting, held at City University, London on 19 December 1994.
SO - Mutat Res 1995 Jul;337(1):61-71
AD - Department of Genetics and Microbiology, University of Liverpool, UK.

4
UI - 7671312
AU - Hartley KO; Gell D; Smith GC; Zhang H; Divecha N; Connelly MA; Admon A;
TI - Lees-Miller SP; Anderson CW; Jackson SP DNA-dependent protein kinase catalytic subunit: a relative of phosphatidylinositol 3-kinase and the ataxia telangiectasia gene product.
SO - Cell 1995 Sep 8;82(5):849-56
AD - Wellcome Trust/Cancer Research Campaign Institute, Cambridge University, England.
DNA-dependent protein kinase (DNA-PK), which is involved in DNA double-stranded break repair and V(D)J recombination, comprises a DNA-targeting component called Ku and an approximately 460 kDa catalytic subunit, DNA-PKcs. Here, we describe the cloning of the DNA-PKcs cDNA and show that DNA-PKcs falls into the phosphatidylinositol (PI) 3-kinase family. Biochemical assays, however, indicate that DNA-PK phosphorylates proteins but has no detectable activity toward lipids. Strikingly, DNA-PKcs is most similar to PI kinase family members involved in cell cycle control, DNA repair, and DNA damage responses. These include the FKBP12-rapamycin-binding proteins Tor1p, Tor2p, and FRAP, S. pombe rad3, and the product of the ataxia telangiectasia gene, mutations in which lead to genomic instability and predisposition to cancer. The relationship of these proteins to DNA-PKcs provides important clues to their mechanisms of action.

5
UI - 8574569
AU - Jackson SP
TI - Cancer predisposition. Ataxia-telangiectasia at the crossroads.
SO - Curr Biol 1995 Nov 1;5(11):1210-2
AD - Wellcome/Cancer Research Campaign Institute, Cambridge University, UK.
ATM, the gene product mutated in the cancer susceptibility syndrome ataxia-telangiectasia, is related to proteins involved in DNA repair and cell-cycle control, perhaps explaining how ATM prevents carcinogenesis.

6
UI - 8808686
AU - Jongmans W; Artuso M; Vuillaume M; Bresil H; Jackson SP; Hall J
TI - The role of Ataxia telangiectasia and the DNA-dependent protein kinase in the p53-mediated cellular response to ionising radiation.
SO - Oncogene 1996 Sep 19;13(6):1133-8
AD - Unit of Mechanisms of Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
The DNA-dependent protein kinase (DNA-PK), whose catalytic subunit shows structural similarities to the Ataxia telangiectasia (AT) gene product (ATM), has also been implicated in the p53-mediated signal transduction pathway that activates the cellular response to DNA damage produced by ionizing radiation. DNA-PK activity however was not found to be related to the transcriptional induction of WAFl/CIP1(p2l) in AT lymphoblastoid cell lines, following treatment with ionizing radiation. Normal protein and transcription levels of Ku70 and Ku80, as well as DNA-PK activity, were found in six different AT cell lines, 1-4 h following exposure to ionizing radiation, timepoints where reduced and delayed transcriptional induction of WAF1/CIP1 (p21) was observed. WAF1/CIP1 (p21) was found to be transcriptionally induced by p53 in normal cell lines over this same time period following exposure to ionizing radiation. These results suggest that despite the findings that in vitro DNA-PK may phosphorylate p53, in vivo it would not appear to play a central role in the activation of p53 as a transcription factor nor can it substitute for the ATM gene product in the cellular response following exposure to ionizing radiation.

7
UI - 9000041
AU - Sullivan KE; Veksler E; Lederman H; Lees-Miller SP
TI - Cell cycle checkpoints and DNA repair in Nijmegen breakage syndrome.
SO - Clin Immunol Immunopathol 1997 Jan;82(1):43-8
AD - Children's Hospital of Philadelphia, Pennsylvania 19104, USA.
Nijmegen breakage syndrome is characterized by a variable T cell and B cell immunodeficiency, growth failure, and an increased risk of malignancy. It is inherited in an autosomal recessive manner and is biochemically related to ataxia-telangiectasia. Cells from a patient with Nijmegen breakage syndrome were unable to arrest cell cycle progression after exposure to ionizing radiation, and BrdU incorporation into newly synthesized DNA was uninhibited, demonstrating that these cells have an aberrant response to radiation exposure. Although gross chromosomal breakage was observed, dinucleotide repeat segments were stable over time, suggesting that other types of DNA stability were not affected. DNA-PK activity, which is mediated by a protein related to the ataxia-telangiectasia gene product and is intimately involved in DNA repair and VDJ recombination, was normal in cells from an NBS patient. Therefore, cells from patients with Nijmegen breakage syndrome have an abnormal response to radiation exposure similar to that seen in ataxia-telangiectasia.

8
UI - 9200331
AU - Danska JS; Guidos CJ
TI - Essential and perilous: V(D)J recombination and DNA damage checkpoints in lymphocyte precursors.
SO - Semin Immunol 1997 Jun;9(3):199-206
AD - Hospital for Sick Children Research Institute, Toronto, ON, Canada.
V(D)J recombination generates a diverse array of antigen-binding specificities, but breakage and re-joining of DNA segments have grave implications for the maintenance of genomic stability and oncogenic risk. Exposure of eukaryotic cells to genotoxic agents activates a DNA damage checkpoint that induces cell-cycle arrest and DNA repair, or apoptosis. We discuss several lines of evidence implicating DNA-dependent protein kinase (DNA-PK), and the gene mutated in ataxia telangiectasia (ATM), two mammalian homologues of yeast DNA damage-checkpoint genes, in regulating the response to intrinsic DNA damage that occurs during V(D)J recombination.

9
UI - 9315668
AU - Maser RS; Monsen KJ; Nelms BE; Petrini JH
TI - hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks.
SO - Mol Cell Biol 1997 Oct;17(10):6087-96
AD - Laboratory of Genetics, University of Wisconsin Medical School, Madison 53706, USA.
We previously identified a conserved multiprotein complex that includes hMre11 and hRad50. In this study, we used immunofluorescence to investigate the role of this complex in DNA double-strand break (DSB) repair. hMre11 and hRad50 form discrete nuclear foci in response to treatment with DSB-inducing agents but not in response to UV irradiation. hMre11 and hRad50 foci colocalize after treatment with ionizing radiation and are distinct from those of the DSB repair protein, hRad51. Our data indicate that an irradiated cell is competent to form either hMre11-hRad50 foci or hRad51 foci, but not both. The multiplicity of hMre11 and hRad50 foci is much higher in the DSB repair-deficient cell line 180BR than in repair-proficient cells. hMre11-hRad50 focus formation is markedly reduced in cells derived from ataxia-telangiectasia patients, whereas hRad51 focus formation is markedly increased. These experiments support genetic evidence from Saccharomyces cerevisiae indicating that Mre11-Rad50 have roles distinct from that of Rad51 in DSB repair. Further, these data indicate that hMre11-hRad50 foci form in response to DNA DSBs and are dependent upon a DNA damage-induced signaling pathway.

10
UI - 9712550
AU - Chan DW; Gately DP; Urban S; Galloway AM; Lees-Miller SP; Yen T;
TI - Allalunis-Turner J Lack of correlation between ATM protein expression and tumour cell radiosensitivity.
SO - Int J Radiat Biol 1998 Aug;74(2):217-24
AD - Department of Biological Sciences, University of Calgary, Alberta, Canada.
PURPOSE: Cells derived from individuals in which the ataxia telangiectasia (ATM) gene is mutated are hypersensitive to ionizing radiation. Whether differences in ATM protein levels exist among human malignant glioma cell lines and whether such differences are correlated with cellular radiosensitivity were determined. MATERIALS AND METHODS: Polyclonal antibodies were raised to separate regions of the ATM protein. ATM protein expression in human malignant glioma cell lines, SV40 transformed normal human fibroblasts and SV40 transformed AT fibroblasts was analysed by Western blotting. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to assess the presence of ATM transcript. RESULTS: While ATM protein was detected in all cell extracts, significant differences in the level of expression were observed. There was no apparent correlation between cellular radiosensitivity and differences in ATM protein levels in these human glioma cells. Extremely low levels of ATM protein were observed in M059J cells, which provide the only example of DNA-dependent protein kinase (DNA-PKcs) deficiency in a cell line of human origin. CONCLUSIONS: Variations in the levels of ATM protein are insufficient to explain the differences in cellular radiosensitivity observed in a panel of human malignant glioma cell lines.

11
UI - 10064605
AU - Shao RG; Cao CX; Zhang H; Kohn KW; Wold MS; Pommier Y
TI - Replication-mediated DNA damage by camptothecin induces phosphorylation of RPA by DNA-dependent protein kinase and dissociates RPA:DNA-PK complexes.
SO - EMBO J 1999 Mar 1;18(5):1397-406
AD - Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Replication protein A (RPA) is a DNA single-strand binding protein essential for DNA replication, recombination and repair. In human cells treated with the topoisomerase inhibitors camptothecin or etoposide (VP-16), we find that RPA2, the middle-sized subunit of RPA, becomes rapidly phosphorylated. This response appears to be due to DNA-dependent protein kinase (DNA-PK) and to be independent of p53 or the ataxia telangiectasia mutated (ATM) protein. RPA2 phosphorylation in response to camptothecin required ongoing DNA replication. Camptothecin itself partially inhibited DNA synthesis, and this inhibition followed the same kinetics as DNA-PK activation and RPA2 phosphorylation. DNA-PK activation and RPA2 phosphorylation were prevented by the cell-cycle checkpoint abrogator 7-hydroxystaurosporine (UCN-01), which markedly potentiates camptothecin cytotoxicity. The DNA-PK catalytic subunit (DNA-PKcs) was found to bind RPA which was replaced by the Ku autoantigen upon camptothecin treatment. DNA-PKcs interacted directly with RPA1 in vitro. We propose that the encounter of a replication fork with a topoisomerase-DNA cleavage complex could lead to a juxtaposition of replication fork-associated RPA and DNA double-strand end-associated DNA-PK, leading to RPA2 phosphorylation which may signal the presence of DNA damage to an S-phase checkpoint mechanism. Keywords: camptothecin/DNA damage/DNA-dependent protein kinase/RPA2 phosphorylation

12
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.

13
UI - 10327072
AU - Piret B; Schoonbroodt S; Piette J
TI - The ATM protein is required for sustained activation of NF-kappaB following DNA damage.
SO - Oncogene 1999 Apr 1;18(13):2261-71
AD - Laboratory of Fundamental Virology and Immunology, University of Liege, CHU, Belgium.
Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.

14
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.

15
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

16
UI - 10677503
AU - Wang S; Guo M; Ouyang H; Li X; Cordon-Cardo C; Kurimasa A; Chen DJ; Fuks
TI - Z; Ling CC; Li GC The catalytic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest.
SO - Proc Natl Acad Sci U S A 2000 Feb 15;97(4):1584-8
AD - Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021; and Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
DNA damage induced by ionizing radiation (IR) activates p53, leading to the regulation of downstream pathways that control cell-cycle progression and apoptosis. However, the mechanisms for the IR-induced p53 activation and the differential activation of pathways downstream of p53 are unclear. Here we provide evidence that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) serves as an upstream effector for p53 activation in response to IR, linking DNA damage to apoptosis. DNA-PKcs knockout (DNA-PKcs-/-) mice were exposed to whole-body IR, and the cell-cycle and apoptotic responses were examined in their thymuses. Our data show that IR induction of apoptosis and Bax expression, both mediated via p53, was significantly suppressed in the thymocytes of DNA-PKcs-/- mice. In contrast, IR-induced cell-cycle arrest and p21 expression were normal. Thus, DNA-PKcs deficiency selectively disrupts p53-dependent apoptosis but not cell-cycle arrest. We also confirmed previous findings that p21 induction was attenuated and cell-cycle arrest was defective in the thymoctyes of whole body-irradiated Atm-/- mice, but the apoptotic response was unperturbed. Taken together, our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate p53 to differentially regulate cell-cycle and apoptotic responses. Whereas Atm selects for cell-cycle arrest but not apoptosis, DNA-PKcs selects for apoptosis but not cell-cycle arrest.

17
UI - 10801460
AU - Petrini JH
TI - The Mre11 complex and ATM: collaborating to navigate S phase.
SO - Curr Opin Cell Biol 2000 Jun;12(3):293-6
AD - University of Wisconsin Medical School, Madison, WI 53706, USA. jpetrini@facstaff.wisc.edu
Recently, findings regarding a group of cancer predisposition and chromosome instability syndromes, Nijmegen breakage syndrome (NBS), the ataxia-telangiectasia-like disorder (A-TLD) and ataxia telangiectasia have shed light on the unexpected role of recombinational DNA repair proteins in DNA-damage-dependent cell-cycle regulation. Mutations in the Mre11 complex cause A-TLD and NBS. In addition, functions of the Mre11 complex have been biochemically linked to ATM, the large protein kinase that is defective in ataxia-telangiectasia cells by the observation that Nbs1 is a bona fide substrate of the ATM kinase.

18
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.

19
UI - 11248063
AU - Sekiguchi J; Ferguson DO; Chen HT; Yang EM; Earle J; Frank K; Whitlow S;
TI - Gu Y; Xu Y; Nussenzweig A; Alt FW Genetic interactions between ATM and the nonhomologous end-joining factors in genomic stability and development.
SO - Proc Natl Acad Sci U S A 2001 Mar 13;98(6):3243-8
AD - The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
DNA ligase IV (Lig4) and the DNA-dependent protein kinase (DNA-PK) function in nonhomologous end joining (NHEJ). However, although Lig4 deficiency causes late embryonic lethality, deficiency in DNA-PK subunits (Ku70, Ku80, and DNA-PKcs) does not. Here we demonstrate that, similar to p53 deficiency, ataxia-telangiectasia-mutated (ATM) gene deficiency rescues the embryonic lethality and neuronal apoptosis, but not impaired lymphocyte development, associated with Lig4 deficiency. However, in contrast to p53 deficiency, ATM deficiency enhances deleterious effects of Lig4 deficiency on growth potential of embryonic fibroblasts (MEFs) and genomic instability in both MEFs and cultured progenitor lymphocytes, demonstrating significant differences in the interplay of p53 vs. ATM with respect to NHEJ. Finally, in dramatic contrast to effects on Lig4 deficiency, ATM deficiency causes early embryonic lethality in Ku- or DNA-PKcs-deficient mice, providing evidence for an NHEJ-independent role for the DNA-PK holoenzyme.

20
UI - 11450971
AU - Tuteja N; Tuteja R
TI - Unraveling DNA repair in human: molecular mechanisms and consequences of repair defect.
SO - Crit Rev Biochem Mol Biol 2001;36(3):261-90
AD - International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
Cellular genomes are vulnerable to an array of DNA-damaging agents, of both endogenous and environmental origin. Such damage occurs at a frequency too high to be compatible with life. As a result cell death and tissue degeneration, aging and cancer are caused. To avoid this and in order for the genome to be reproduced, these damages must be corrected efficiently by DNA repair mechanisms. Eukaryotic cells have multiple mechanisms for the repair of damaged DNA. These repair systems in humans protect the genome by repairing modified bases, DNA adducts, crosslinks and double-strand breaks. The lesions in DNA are eliminated by mechanisms such as direct reversal, base excision and nucleotide excision. The base excision repair eliminates single damaged-base residues by the action of specialized DNA glycosylases and AP endonucleases. Nucleotide excision repair excises damage within oligomers that are 25 to 32 nucleotides long. This repair utilizes many proteins to remove the major UV-induced photoproducts from DNA, as well as other types of modified nucleotides. Different DNA polymerases and ligases are utilized to complete the separate pathways. The double-strand breaks in DNA are repaired by mechanisms that involve DNA protein kinase and recombination proteins. The defect in one of the repair protein results in three rare recessive syndromes: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. This review describes the biochemistry of various repair processes and summarizes the clinical features and molecular mechanisms underlying these disorders.

21
UI - 11765064
AU - Gatti RA
TI - The inherited basis of human radiosensitivity.
SO - Acta Oncol 2001;40(6):702-11
AD - Department of Pathology, UCLA School of Medicine, Los Angeles, CA 90095-1732, USA. rgatti@mednet.ucla.edu
Certain individuals cannot tolerate 'conventional' doses of radiation therapy. This is known to be true of patients with ataxia-telangiectasia and ligase IV deficiency. Although in vitro testing may not correlate completely with clinical radiosensitivity, fibroblasts and lymphoblasts from patients with both of these disorders have been clearly shown to be radiosensitive. Using a colony survival assay (CSA) to test lymphoblastoid cells after irradiation with 1 Gy, a variety of other genetic disorders have been identified as strong candidates for clinical radiosensitivity, such as Nijmegen breakage syndrome, Mre 11 deficiency, and Fanconi's anemia. These data are presented and considered as a starting-point for the inherited basis of human radiosensitivity.

22
UI - 11741320
AU - Theard D; Coisy M; Ducommun B; Concannon P; Darbon JM
TI - Etoposide and adriamycin but not genistein can activate the checkpoint kinase Chk2 independently of ATM/ATR.
SO - Biochem Biophys Res Commun 2001 Dec 21;289(5):1199-204
AD - Laboratoire de Biologie Cellulaire et Moleculaire du Controle de la Proliferation, UMR 5088 CNRS, Universite Paul Sabatier, Bat 4R3B1, 118 route de Narbonne, Toulouse, 31062, France.
We have investigated the effects of three unrelated topoisomerase 2 inhibitors, genistein, adriamycin, and etoposide, on phosphorylation/activation of the checkpoint kinase Chk2 in normal or ATM-deficient (ATM-) human fibroblasts and in cells overexpressing a catalytically inactive ATR kinase. We demonstrate that genistein activates Chk2 in a strictly ATM-dependent manner, whereas etoposide and adriamycin can trigger Chk2 activation in long-term cultures of ATM- cells. Moreover, these two latter genotoxic compounds were found to activate Chk2 in fibroblasts expressing the dominant negative form of ATR. We also report a significant decrease in the accumulation in G2-phase of ATM- cells when genistein did not activate Chk2. In conclusion, our results strongly support that activation of Chk2 could be dependent on the type and/or extent of DNA damage and under the control of either an ATM-dependent or an ATM and, maybe, an ATR-independent pathway.

23
UI - 11805335
AU - Scott SP; Bendix R; Chen P; Clark R; Dork T; Lavin MF
TI - Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer.
SO - Proc Natl Acad Sci U S A 2002 Jan 22;99(2):925-30
AD - Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Brisbane 4029, Australia.
The human genetic disorder ataxia-telangiectasia (A-T) is characterized by hypersensitivity to ionizing radiation and an elevated risk of malignancy. Epidemiological data support an increased risk for breast and other cancers in A-T heterozygotes. However, screening breast cancer cases for truncating mutations in the ATM (A-T mutated) gene has failed largely to reveal an increased incidence in these patients. It has been hypothesized that ATM missense mutations are implicated in breast cancer, and there is some evidence to support this. The presence of a large variety of rare missense variants in addition to common polymorphisms in ATM makes it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes we have introduced missense substitutions, identified in either A-T or breast cancer patients, into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in A-T cells. Furthermore missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. This approach represents a means of identifying genuine ATM mutations and addressing the significance of missense changes in the ATM gene in a variety of cancers including breast cancer.

24
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.

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