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Abramson Cancer CenterNCI CANCERLIT® Search: Ataxia Telangiectasia - April 2002
National Cancer Institute®
Last Modified: April 1, 2002
Table of Contents
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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