LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
1.5 Charged particle irradiation induced Signaling
Apart from X-rays, biological effects from particulate radiation are of immense interest
due to their use in treatment of certain solid tumors and also due to their abundance in
space. High LET radiations, such as heavy ions or neutrons, have an increased biological
effectiveness compared to X-rays for gene mutation, genomic instability and
carcinogenesis. The amount of induction of DSBs is weakly dependent on LET of the
radiation [205]. However, the degree of lesion complexity increases with increasing LET
[206]. There has been a consensus about the clustering of damage in case of high LET
radiation along individual radiation tracks crossing the DNA
The extensive studies using synthetic clustered DNA lesions have largely contributed to
our understanding of the biological consequences of clustered lesions in cells or tissues.
Clustered damage sites are of large diversity, they are processed differently depending on
the nature of the base modification, the inter lesion spacing, the presence or not of strand
breaks. The expected biological consequences range from point mutations and loss of
genetic material to cellular lethality due to repair impairment and lesion or repairintermediate
persistency (Fig. 1.5) In fact, the deleterious effect of repair intermediates
may be amplified at replication and cause cell killing. Tandem lesions have been isolated
and have been shown to be poorly repaired or by-passed by DNA polymerases, and may
be lethal lesions. Bistranded AP sites are more likely to result in DSBs, the outcome of
which will depend on the presence of damage bases around the DSB, and subsequent
deletions have been observed in human cells. The repair of bistranded oxidized bases is
mostly impaired, causing a point mutation at the unrepaired damaged base. DSBs are
unlikely to be formed by BER at these clusters, but may occur at replication forks if the
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