Relazione tra il background genetico e la risposta cellulare in seguito al danno primario al DNA
Author(s)
Ortenzi, Vincenza
Date Issued
March 8, 2011
Type
Doctoral Thesis
Abstract
Exposure to ionizing radiation and other genotoxic agents induces DNA damage (e.g.,
double strand breaks, DSBs). The cells can trigger DNA repair, cell cycle arrest and
programmed cell death to maintain genomic integrity. These events depend on the phase of
the cycle, the exposure, the environment, the extent of the damage and the radiosensitivity of
the particular cellular system under analysis. The cellular response involves a complex
"network" of events inducing mechanisms able to rejoin DNA DSBs, that can lead to changes
in gene expression profiles and tumorigenesis.
The purpose of this work is to study the relationship between genetic background and
the cellular response after primary DNA damage. In particular, we studied the cellular
response after X-rays exposure in Ataxia Telangiectasia (AT) lymphoblastoid cell lines that
differ for several mutations in the ATM gene. AT is a rare genetic neurodegenerative disease,
caused by the lack of functional ATM kinase. In this context, we focused on the role of some
proteins, such as p53, on repair of DNA damage, by means its inhibitor pifithrin-a (PFT-a).
The stability genomic control has also been studied in human cell lines such as
lymphocytes and primary fibroblasts, after exposure to ionizing radiation in different phases
of the cell cycle. Other studies described in literature suggest that apoptosis has a selective
role in the removal of cells bearing unstable chromosomal aberrations (dicentrics). The two
cellular systems are very different in terms of anatomical and histological functions, and these
differences are also reflected in their neoplastic phenotypes. The fibroblast cell system,
chosen for this work, allows to compare the results with those obtained in the lymphocytes.
In addition, preliminary studies on the induction of histone variant g-H2AX have been
led on Chinese hamster cell lines. In particular the analysis was focused on g-H2AX foci
induced by different chemical and physical agents in order to relate the type of DNA damage
caused by different agents and its subsequent repair and to determine the involvement of
histone H2AX at the various stages that lead to the resolution of DNA damage.
By the analysis of the collected data, we can conclude that the cellular response differs
depending on cell type, the phase of the cell cycle when DNA damage occurs, the agent used
for its induction and the several mutations in the defective gene. Therefore this study shows
the importance of studying the cellular response and how this response controls the genomic
stability. This has relevance not only in basic research but also in the field of potential anticancer
therapy or treatment for genetic syndromes with genomic instability, such as Ataxia
Telangiectasia.
Additional information
Dottorato di ricerca in Evoluzione biologica e biochimica
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