LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 4
DISCUSSION
A clear cause and effect relationship was established between DNA damage signaling,
gene expression and efficient DNA repair and was evident in the form of cell survival in A549
cells that had been exposed to fractionated irradiation.
It has been reported that A549 cells are relatively more radioresistant than MCF-7 cells if
radiation dose was delivered as fractionated regimen [254]. But the mechanism of such response
has not been studied. To best of my knowledge this is the first study explaining the mechanism
of such response as activation of repair pathway, efficient DNA repair and translocation of
phospho-p53 into the nucleus of A549 cells exposed to fractionated irradiation and not in MCF-7
cells exposed to fractionated irradiation (Fig. 3.1.8).
The level of mRNA expression is known to be modulated through transcriptional and
posttranscriptional control mechanisms. An important posttranscriptional control is exerted on
mRNA stability, which varies considerably from one mRNA species to another and can be
modulated by various stimuli such as radiation [255-257].How these stimuli influence mRNA
halflives in ways that are incompletely understood. Although much has been researched about
radioresistance and DNA damage, surprisingly there are absolutely no reports on the stabilization
of mRNA of crucial DNA damage and maintenance of proteins. It is quite likely that mRNA
stabilization could contribute to the development of radio resistance. The expression of DNA-PK
was partly due to up-regulation of DNA-PK transcriptional activity to some degree, DNA-PK
mRNA stabilization played important roles in maintaining high DNA-PK expression level in this
study (Fig. 3.1.9). The ATM and Rad52 mRNA were not stabilized indicating a specific and
selective stabilization of DNA-PK mRNA. The DNA-PK mRNA stabilization was mediated by
p38 MAP kinase signaling pathways but not by ERK or JNK MAP Kinase pathway (Fig. 3.1.9).
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