LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
1.3 DNA damage signaling following irradiation
The pathways that signal DNA damage can be envisioned as transduction cascades in
which the DNA lesion acts as the signal. Much of our understanding of these pathways is
based on genetic studies of the yeasts Saccharomyces cerevisiae and
Schizosaccharomyces pombe; these studies have identified a series of genes crucial for
signaling. There are mammalian homologues of virtually all of these genes, indicating
that DNA damage signaling is highly conserved.
In all organisms examined, signaling involves proteins of the phosphatidylinositol 3-
kinase-like (PIKK) family — ATR and ATM in humans, Mec1p and Tel1p in S.
cerevisiae, and Rad3 and Tel1 in S. pombe. The prevailing view is that DNA damage
somehow activates these kinases, which then amplify and channel the signal by activating
downstream kinases (hChk1 and hChk2 in humans). These, in turn, phosphorylate target
proteins such as p53, Cdc25A and Cdc25C [9-11] to delay the cell cycle, a process called
the DNA damage checkpoint. In addition to checkpoint control, the downstream kinases
also modulate DNA repair and trigger apoptosis [12, 13].
1.3.1 Alarm Sensors
The first response to radiation induced DNA damage is the activation of the alarm
sensors. As the name indicates, these are proteins which detect the damage and set off the
alarm signals, thereafter, the cell readies itself for subsequent action. Interestingly, it is
the proteins involved in DNA repair, like (DNA-PK, ATR, ATM, BRCA-1, PARP etc.),
which scan the genome, detect the damage and act as alarm sensors.
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