Role of Apoptosis in the final outcome of DNA damage
Author(s)
Belloni, Paola
Date Issued
April 11, 2008
Type
Doctoral Thesis
Abstract
Damage to DNA is intrinsic to life, as the cell continuosly suffers from numerous
exogenous agents, including radiation and chemicals, and from endogenous sources, such as
free radicals generated during essential metabolic processes. The broad spectrum of DNA
lesions induced by these agents includes damage to nucleotide bases, DNA protein crosslinks
and DNA single- and double-strand breaks (DBSs). Because of their high cytotoxicity
(unrepaired or misrepaired DNA DSBs can kill a cell) and their ability to induce
chromosomal aberrations (that may ultimately lead to carcinogenesis) cell survival and
mantenaince of genome integrity are critically dependent on efficient repair of DNA DSBs.
When the burden of genomic insult is too large to be effectively repaired, cells are able to
initiate apoptosis (programmed cell death). On the basis of these considerations, the aim of
this thesis has been to investigate the role of apoptosis in the final outcome of DNA damage.
Since G0 lymphocytes are the most common tissue used in biodosimetry studies, and
the amount of chromosomal damage detected depends on the time between exposure and
sampling, it was of interest to investigate the relationship between the frequencies of
radiation induced chromosomal aberrations and the extent of apoptosis in G0 human
lymphocytes (Paper I). In human lymphocytes irradiated in G0 without subsequent
stimulation to proliferate, a p53-dependent apoptotic pathway preferentially eliminates cells
bearing unstable aberrations.
Studies in Paper II demonstrated that in human lymphocytes the type of chromosome
damage influences the induction of programmed cell death and provided direct evidence that
cells bearing dicentric chromosomes are eliminated by apoptosis.
The lymphocytes undergo apoptosis during storage, and this loss of viability is
accelerated by increasing both temperature and storage time, was demonstrated in Paper III.
Studies on the effects of storage conditions of whole blood on the viability and proliferation
of lymphocytes revealed optimal the storage at 4°C for 96 h in the presence of
phytohaemagglutinin.
The influence of genetic background on the induction of apoptosis in cells of different
origin, treated with a potential anticancer drug “STDS2323”, was studied in Paper IV.
In conclusion, this thesis suggests that apoptosis has an important role in the final
outcome of DNA damage. The thesis further suggests that these results may have relevance
for biodosimetrical and molecular epidemiological studies and in evaluations of the efficacy
of radio- and chemotherapy.
Additional information
Dottorato di ricerca in Evoluzione biologica e biochimica
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