LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 4
DISCUSSION
the mechanism for early activation of these kinases [277]. ATM has been shown to enhance
repair via activation of ERK pathway [251] and inhibition of JNK [278]. Observed activation of
ERK (Fig.3.3.1.7a) but not JNK (Fig.3.3.1.7b) in gamma irradiated cells indicated the dominance
of pro-survival pathways.
Since, with high LET radiation yield of ROS is very low because of the radical-radical
recombination, the early activation of ERK was not expected. However, complete absence of
ERK activation even hours after high LET radiation suggests that repair pathways are neither
feeding into nor being fed upon by intracellular cytoprotective signaling. However, the proapoptotic
JNK pathway was found to be activated after high LET radiation. BRCA1 induced
apoptotic responses have also been shown to be via activation of JNK [279]. Thus, after carbon
irradiation, DNA damage induced activation of repair components are being fed into by
cytotoxic signaling rather than cytoprotective responses and was evident in the form of early
induction of apoptosis (Fig.3.3.1.8). Since, cellular decisions are summation of all the activated
pathways, the final response after high LET radiation tips towards death.
In summary, these results suggest that the subtle differences leading to different outcomes due to
radiation quality seem to lie in different macromolecular complexes of crucial DNA damage
response proteins and activation of other intracellular pathways. Analysis of functionality of
these macromolecular complexes as a whole rather than individual proteins and holistic study
involving intracellular survival pathways could help in revealing the mechanistic details of
complex DNA damage responses.
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