LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
occurs at DSBs, suggesting that the proteins co-localize at sites of DNA damage [86].
Together, these studies suggest an attractive model in which (i) the MRN complex binds
directly to damaged DNA, (ii) Mre11 processes the DNA ends, (iii) ATM is recruited and
activated through autophosphorylation and monomerization, and (iv) kinase-active,
monomeric ATM phosphorylates substrates present at, or recruited to, the DSB. Once
activated, ATM may be released from the site of the DSB, enabling phosphorylation of
more distal substrates, such as chromatin-bound histone H2AX. This might account for
the rapid DNA damage-induced phosphorylation of histone H2AX that occurs over
several megabases surrounding the site of a DSB [87]. Indeed, the downstream
checkpoint protein kinase Chk2 is recruited only transiently to sites of DNA damage [86].
It remains to be seen whether this is the only mechanism for activation of ATM by all
DNA-damaging agents, or whether ATM can, under some circumstances, be activated by
direct DNA binding, or by interaction with other DNA-binding partners. A very recent
report suggests that the mediator of DNA damage checkpoint protein, MDC1 (also called
NFBD1), which is known to interact with the MRN complex [88], is required for MRNdependent
activation of ATM at high doses of IR, whereas the p53-binding protein
53BP1 is required for activation of ATM at low doses of IR [89], suggesting that
additional proteins may indeed regulate the activation of ATM. Another fascinating clue
to emerge in recent years is that the BRCA1 protein is required for IR-induced
phosphorylation of some ATM substrates, including p53, c-jun, Nbs1, and Chk2 [90].
BRCA1 is also required for phosphorylation of p53 on serine 15 at later times after DNA
damage in A-T cells, consistent with a requirement of BRCA1 for some ATR-mediated
events [90]. In addition, BRCA1 is required for IR-induced phosphorylation of the
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