LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
compensate for loss or dysfunction of ATM. However, the inter-relationship between the
various PIKK family members remains to be clarified.
Despite the abundance of physiological substrates of ATM, one of the most
frequently used “read-outs” of ATM activity is the phosphorylation of p53 on serine 15.
IR-induced phosphorylation of p53 is both attenuated and delayed in A-T cells [109].
However, serine 15 phosphorylation of p53 is clearly evident in ATM-deficient cell lines
at later times after exposure to IR, indicating that ATM is required for serine 15
phosphorylation predominantly during the initial phase of the DNA damage response,
and that other serine 15 specific protein kinases, such as ATR, can probably compensate
for the absence of ATM at later times [109]. IR also induces phosphorylation of p53 at
serines 6, 9, 20, 33, 46, 315, and 392, and ATM is required for efficient phosphorylation
on serines 9, 20, and 46, as well as 15 [110]. Indeed, phosphorylation of p53 on serines
20 and 46 is far more dependent on the presence of ATM than is phosphorylation on
serine 15 [110]. Therefore, in studying the requirement for ATM in the cellular response
to a given stressor, the analysis of other ATM-dependent p53 phosphorylation sites, in
particular serines 20 and 46, may be informative. Although p53 is an important target of
ATM, activation of ATM results in the phosphorylation of many other substrates and
regulation of multiple cellular processes. Therefore, analysis of the ATM-dependent
phosphorylation of one substrate cannot provide an accurate picture of the complexity of
a given cellular response. A thorough understanding of the role of ATM will require a
multifactorial approach in which the expression, activity, and phosphorylation of multiple
substrates are analyzed both temporally and spatially. As discussed above, ATM is
predominantly required for the initial response to DNA damage; therefore, time after
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