LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
related protein kinase, ATR, signaled to Chk1. Recent studies, however, have
demonstrated that IR induces ATM-dependent phosphorylation of Chk1 on serine 317
[102] and serine 345 [100], suggesting that ATM and ATR-dependent signaling pathways
could overlap rather than exist in parallel as originally proposed. The most well
characterized cellular response to activation of ATM is activation of G1/S, intra-S, and
G2/M cell cycle checkpoints. However, ATM also plays important roles in other aspects
of the DNA damage response. One of the primary functions of cell cycle arrest may be to
allow the cell more time to repair DNA damage. Thus, activation of ATM-dependent cell
cycle checkpoints would be expected to engage mechanisms for the repair of IR-induced
DNA damage. A very recent study [103], suggests that one way in which this occurs is
via ATM-dependent, Chk2-mediated phosphorylation of BRCA1 on serine 988, and
upregulation of DSB repair via homologous recombination [103, 104]. It is also possible
that ATM-dependent activation of c-Abl [101] and c-Abl-induced phosphorylation of
Rad51 on tyrosine 315 [105], play a role in regulation of DSB repair. c-Abl also
phosphorylates BRCA1 in an ATM-dependent manner [106], while BRCA1 interacts
with BRCA2 which, in turn, interacts with Rad51 [107]. In addition, ATM also
influences DNA damage-induced changes in gene expression through its effects on the
IKK/NF-КB pathway [99] and possibly c-jun [90]. How ATM regulates DNA damageinduced
apoptosis is still uncertain. One possibility is via p53-mediated upregulation of
pro-apoptotic genes, such as Noxa and Puma [108]. Given the importance of ATM in the
cellular response to DSBs, it is perhaps surprising that ATM is not an essential gene in
mammalian cells. This likely reflects the fact that other members of the PIKK family,
such as ATR, DNA-PKcs, or ATX, have similar substrate specificities and may be able to
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