Table of Contents
1
UI - 21460697
AU - Brammer I; Zoller M; Dikomey E
TI -
Relationship between cellular radiosensitivity and DNA damage measured
by comet assay in human normal, NBS and AT fibroblasts.
SO - Int J Radiat Biol 2001 Sep;77(9):929-38
AD - Institute of Biophysics and Radiobiology, University of Hamburg,
Martinistr. 52, D-20246, Hamburg, Germany. brammer@uke.uni-hamburg.de
PURPOSE: To study the relationship between cellular radiosensitivity and
DNA damage measured by the comet assay. MATERIALS AND METHODS:
Experiments were performed with nine human fibroblast lines (six normal,
one NBS, and two AT). Cellular radiosensitivity was determined by colony
assay and DNA damage was assessed by the comet assay. RESULTS: The
cellular radiosensitivity of the fibroblast lines used covered a broad
range with SF2 values varying between 1.3% and 53%. The comets analysed
immediately after irradiation with doses up to 5 Gy showed marked
differences among the cell lines; the relative initial tail moment at a
dose of 5 Gy, ITM5, varied from 2.7+/-0.2 to 5.0+/-0.3. This variation
was considered not to result from different numbers of DNA strand breaks
induced but from differences in chromatin structure. There was an
inverse correlation between SF2 and ITM5, i.e. radiosensitive cell lines
exhibited a higher initial tail moment than radioresistant cell lines.
In contrast, the repair kinetics measured with the comet assay for a
dose of 2Gy followed by an incubation of up to 2h showed little
variation and were found not to correlate with SF2. Repair kinetics as
well as the amount of residual damage measured by this version of the
comet assay were fairly similar to those measured by the alkaline
unwinding technique and unlike that measured by neutral gel
electrophoresis, indicating that this comet assay detects primarily
single-strand breaks and alkali-labile sites, not double-strand breaks.
CONCLUSIONS: The correlation between SF2 and the initial tail moment at
5 Gy found here suggests that the cellular radiosensitivity of human
fibroblasts also depends on the chromatin structure.
2
UI - 21010702
AU - Asaad NA; Zeng ZC; Guan J; Thacker J; Iliakis G
TI -
Homologous recombination as a potential target for caffeine
radiosensitization in mammalian cells: reduced caffeine
radiosensitization in XRCC2 and XRCC3 mutants.
SO - Oncogene 2000 Nov 23;19(50):5788-800
AD - Department of Radiation Oncology of Kimmel Cancer Center, Jefferson
Medical College, Philadelphia, Pennsylvania 19107, USA.
The radiosensitizing effect of caffeine has been associated with the
disruption of multiple DNA damage-responsive cell cycle checkpoints, but
several lines of evidence also implicate inhibition of DNA repair. The
role of DNA repair inhibition in caffeine radiosensitization remains
uncharacterized, and it is unknown which repair process, or lesion, is
affected. We show that a radiosensitive cell line, mutant for the RAD51
homolog XRCC2 and defective in homologous recombination repair (HRR),
displays significantly diminished caffeine radiosensitization that can
be restored by expression of XRCC2. Despite the reduced
radiosensitization, caffeine effectively abrogates checkpoints in S and
G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is
not sufficient for radiosensitization. Another radiosensitive line,
mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine
radiosensitization. On the other hand, a radiosensitive mutant (irs-20)
of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is
radiosensitized by caffeine to an extent comparable to wild-type cells.
In addition, rejoining of radiation-induced DNA DSBs, that mainly
reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3
mutants, or their wild-type counterparts. These observations suggest
that caffeine targets steps in HRR but not in NHEJ and that abrogation
of checkpoint response is not sufficient to explain radiosensitization.
Indeed, immortalized fibroblasts from AT patients show caffeine
radiosensitization despite the checkpoint defects associated with ATM
mutation. We propose that caffeine radiosensitization is mediated by
inhibition of stages in DNA DSB repair requiring HRR and that checkpoint
disruption contributes by allowing these DSBs to transit into
irreparable states. Thus, checkpoints may contribute to genomic
stability by promoting error-free HRR.
3
UI - 21374349
AU - Klein C; Stewart GS; Quinn NP; Taylor AM
TI -
Ataxia without telangiectasia revisited: update on genetic findings in
two brothers with an ataxia-telangiectasia-like disorder.
SO - Mov Disord 2001 Jul;16(4):788-9
4
UI - 21398709
AU - Pincheira J; Bravo M; Navarrete MH; Marcelain K; Lopez-Saez JF; de la
TI -
Torre C
Ataxia telangiectasia: G2 checkpoint and chromosomal damage in
proliferating lymphocytes.
SO - Mutagenesis 2001 Sep;16(5):419-22
AD - Programa de Genetica Humana and Departamento de Pediatria y Cirugia
Infantil, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
There is a checkpoint pathway in eukaryotic cells that depends on ATM
(ataxia telangiectasia mutated) kinase which activates the processes
leading to the repair of DNA damage and also lengthens the G(2) stage of
the cell cycle. In cells from ataxia telangiectasia patients, due to
their lack of active ATM kinase, an increase in chromosomal aberrations
and a failure to induce G(2) lengthening could be expected. However, the
basal G(2) timing in ataxia telangiectasia cells was longer than in
controls and was further extended after X-ray irradiation (0.4 Gy),
although to a lesser extent than in controls. Moreover, in control cells
caffeine shortened G(2) and increased chromosomal damage 7-fold, while
in ataxia telangiectasia cells caffeine only trebled aberration yield
without shortening G(2). As caffeine is an inhibitor of ATM kinase,
these results suggest the existence of some redundant ATM-independent
checkpoint in G(2) of ataxia telangiectasia cells. The differential
response to caffeine of ataxia telangiectasia and control lymphocytes
may be explained by the presence of two different subpathways in the
G(2) checkpoint: one regulating the processing and repair of damaged DNA
and the other controlling G(2) timing. While in controls both
subpathways may be mediated by ATM kinase, in ataxia telangiectasia
cells caffeine-sensitive ATR kinase and the caffeine-insensitive DNA-PK
kinases might be responsible for DNA repair and the G(2) delay
subpathways, respectively. Confirmation of this model in ataxia
telangiectasia cells with another cell type in which both subpathways
are mediated by DNA-PK should define whether a metylxanthine such as
caffeine may also have an additional direct inhibitory effect on DNA
repair.
5
UI - 21398713
AU - Menendez D; Mora G; Salazar AM; Ostrosky-Wegman P
TI -
ATM status confers sensitivity to arsenic cytotoxic effects.
SO - Mutagenesis 2001 Sep;16(5):443-8
AD - Instituto de Investigaciones Biomedicas, UNAM, Apartado Postal 70228,
D.F., Mexico City 04510, Mexico.
Arsenic (As), a human carcinogen, represents a worldwide health problem
due to the high number of people exposed to this element in their
drinking water. Previously our group has demonstrated that As can impair
lymphocyte cell proliferation in vitro and in vivo and can increase the
level of P53 protein, with different responses to these effects between
individuals. Recently it has been shown that ATM protein, responsible
for the autosomal recessive disorder ataxia telangiectasia (AT),
regulates P53. In this study the induced response of P53 was evaluated
following exposure to As in human lymphoblastoid cell lines normal
(+/+), heterozygous (+/-) or homozygous (-/-) for the mutant ATM gene.
After 24 h As treatment we found a dose-dependent induction of P53 in
normal and heterozygous cell lines, although differences between cell
lines were observed. An increase in P21(WAF) protein, a main effector of
P53 activation, was also observed in the same cell lines. In contrast,
neither P53 nor P21 induction was detected in homozygous cells. The ATM
(+/-) and (-/-) genotypes confer more sensitivity to As cytotoxic
effects than the normal allelic condition. Paradoxically, ATM
heterozygous cells were more sensitive to As, leading us to propose that
this might be related to activation of apoptosis and removal of
non-repairable cells. In contrast, in AT cells in which ATM is absent or
mutated activation of P53 and its target genes is abrogated, allowing
cells to replicate with damage in the presence of As, with cell death
ensuing by a pathway different from P53.
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