LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
cycle-specific fashion and the former is a target for the ATM protein kinase [144]. ATM
and the tyrosine kinase c- Abl protein appear to be central to the control of DSB repair.
The c-Abl protein is itself activated by phosphorylation. This appears to be achieved by
its interaction with the ATM protein [149]. Human Rad51 is phosphorylated by c-Abl,
possibly via the formation of a tripartite complex with the ATM protein [105]]. ATM/c-
Abl-dependent phosphorylation promotes the interaction between hRad51 and hRad52,
suggesting that the HR recombination repair pathway is subject, at least in part, to fine
control by these interactions. c-Abl is also implicated in activation of c-Jun aminoterminal
kinase. Significantly, this activation is impaired in Nbs1 (and hMre11) as well as
ATM-defective human cells. The ATM protein is implicated in the p53-related DNA
damage response. p53 plays a crucial role in determining the fate of cells in which DSBs
persist. In particular, the embryonic lethality of both the Rad51 null [136] and Brca1 null
[148] animals is attenuated in a p53–/– background and some double knockout animals
survive to full term. This suggests that the massive failure of cellular proliferation, which
is a feature of Rad51–/– and Brca1–/– embryos, is to some degree a direct consequence
of an active p53. Put another way, cells which fail to repair DSBs by the Rad51- and
Brca1-dependent HR pathways die in a p53-dependent fashion. Promoting the deletion of
cells which might otherwise perform mutation-prone DSB repair may be a facet of p53’s
role as ‘guardian of the genome’.
1.3.3.2Single strand DNA repair
Nucleotide excision repair (NER) repairs DNA with helix-distorting damages, including
the damages of cyclobutane pyrimidine dimers and 6–4 photoproducts produced by UV
light, and adducts produced by the chemotherapeutic agents cisplatin and 4-
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