LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
At the present, much insight is being gained regarding the roles of p53 in DSB repair.
Further studies on p53 functioning as the switch from reversible arrest to triggering
apoptosis may offer a greater understanding of radioresistance and radiosensitivity [111].
p21
p21 Waf1/Cip1/Sdi1 is the first identified inhibitor of cyclin/cyclin-dependent kinase (CDK)
complexes, which regulate transitions between different phases of the cell cycle. p21 was
independently isolated as a CDK-binding protein and as a growth-inhibitory gene which
is upregulated by wild-type p53 [112] or overexpressed in senescent fibroblasts [113].
Although many other CDK inhibitors have since been discovered [114], p21 appears to
be the only inhibitor capable of interacting with essentially all of the CDK complexes.
The effects of p21 on CDKs, however, are not limited to simple binding and inhibition.
For example, p21 binding, depending on its stoichiometry, may not only inhibit but also
stimulate CDK4/6 complexes [115]. On the other hand, p21 affinity towards
CDC2/CDK1 (the primary regulator of cellular entry into mitosis) is low, suggesting that
p21 may not bind CDC2 under physiological conditions [116]. Nevertheless, p21
expression efficiently inhibits CDC2 in vivo; this effect appears to be mediated at least in
part through the interference with the activating phosphorylation of CDC2 at Thr 161 [117,
118].
The first transcriptional target of p53 identified was the Cdk inhibitor p21. That p53
transactivation of p21 does not necessarily yield increased p21 protein levels is another
important aspect of the study described by Jascur et al. [119]. DNA damage by ionising
radiation results in stabilization of wild-type p53 and subsequent transcriptional
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