LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 4
DISCUSSION
slow repair. DNA repair pathways activated by charged particle radiation might be different from
those studied after gamma irradiation.
Likewise, there was significantly higher phosphorylation of ATM at serine 1981 in A549 cells
that had been exposed to proton beam (Fig.3.2.3), indicating the fact that despite significant
activation of ATM (4 hours) much of the damage still persisted. The activated/phosphorylated
ATM would further phosphorylate various downstream target proteins such as H2AX, Chk2, p53
etc. leading to opening of the chromatin and recruitment of other proteins involved in DNA
repair or cell cycle arrest.
Phosphorylation of Chk2 indicated that small component of ATM activation is also diverted to
cell cycle arrest pathways such as Chk2, CDC25 phosphatase and CDKs. These could also be
involved in activation of other proteins such as BRCA1 and p53. Phosphorylation of p53 at
serine 15 was then observed in unirradiated and irradiated A549 cells at 2Gy of proton beam
(Fig.3.2.3). These results indicated cell cycle arrest in A549 cells exposed proton beam.
Whether DNA-PK signals DSBs to the checkpoint machinery remains controversial, but the
emerging consensus is that it does not [22]. DNA-PK may, however, be involved in signaling
DNA damage to the apoptosis machinery [24].
The degree of radiation-induced apoptosis has been shown to correlate with the p53 wild-type
status [265]. In addition, apoptosis is induced when wild-type p53 is transfected into certain cell
lines lacking p53 [266]. This indicates that p53 not only plays a role in regulating the progression
through the cell cycle, it can also induce apoptosis in cells. p53 is not an essential component of
the machinery that carries out apoptosis; however, it appears to be an activator of apoptosis.
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