LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
Early observations showed that densely ionizing radiation like high LET radiation was
more cytotoxic than sparsely ionizing radiation and it was anticipated that a greater
proportion of non-repairable strand breaks originating from clustered lesions was
responsible for the increased biological effectiveness of densely ionizing radiation.
Larger proportions of DSBs remain unrejoined after exposure to high LET radiation than
after exposure to sparsely ionizing radiation, and chromosomal damage is more severe
and complex. The frequency of chromosome breaks and of complex rearrangements
increases up to a LET of 100–150 keV/µm and seems to plateau at higher LETs. In most
cellular systems examined but not all, high LET radiation is observed to generate larger
deletions (over Mbp size). A high frequency of complex deletion events and complex
rearrangements at deletion junctions have been observed with high LET radiation and
have not been reported for low LET radiation [207-209]. Notably, an unusually high
proportion of radon-induced mutants exhibited two or more base substitutions and
insertions/deletions within 3–14 bp at the HPRT locus in T lymphocytes and this has
been suggested as a signature of exposure to densely ionizing radiation [210]. The
carcinogenic potential of high LET radiation has also been proven. In addition, exposures
to densely ionizing radiation have been shown to lead to a persistent, transmissible
genomic instability in a variety of biological systems. With regard to DNA repair, it has
recently been shown that DNA-PKcs participates in the repair of some frank DSBs and
some non-DSB clustered damages that are converted into DSB by replication in tumor
cells exposed to high LET radiation [211]. In addition, intact homologous recombination
is also required to ensure DNA repair and cell survival after exposure to high-energy iron
ions [212]. It appears that the biological features specific to high LET radiation do relate
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