LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
structural maintenance of chromosomes protein, SMC1 [91], Chk1 [92], and, is itself a
substrate of ATM[93]. However, BRCA1 is not required for the activation of ATM (as
judged by ATM activity in IP kinase assays) [90]. DNA damage-induced phosphorylation
of histone H2AX and human Rad17 (which recruits the Hus1–Rad1–Rad9 complex) also
do not require the presence of BRCA1 [90]. Together, these studies suggest that BRCA1
acts as a scaffolding protein that makes some, but not all, non-chromatin-associated
substrates accessible to the activated ATM protein [90]. BRCA1 has also been identified
as part of a larger protein complex, BRCA1-associated genome surveillance complex
(BASC), which contains ATM, the mismatch repair proteins MSH2, MSH6, MLH1, the
Bloom syndrome helicase (BLM), the MRN complex, and replication factor C (RFC)
[94], but how BASC functions in the DNA damage response remains to be determined.
BRCA1 contains two carboxy-terminal BRCT repeats, motifs that have been shown
recently to bind phosphoproteins [95-97]. It is, therefore, possible that phosphorylation of
BRCA1 could regulate its association with partner proteins, and thus, further regulate
phosphorylation of BRCA1-associated proteins by ATM. Interestingly, BRCA1 has also
been shown to interact with protein phosphatase 1α [98], providing another possible
mechanism for regulation. Activation of ATM results in the phosphorylation of a plethora
of downstream targets. Some of these proteins are direct substrates of ATM, for example,
ATM likely directly phosphorylates serine 15 of p53 and serine 139 of histone H2AX in
response to DNA damage. Others may be phosphorylated indirectly, through ATMmediated
regulation of other protein kinases, such as Chk1, Chk2 [29, 60], IКB kinase
(IKK) [99], LKB1 [100], c-Abl [101], and the cyclin-dependent protein kinases (cdk1
and cdk2). It was previously thought that ATM signaled directly only to Chk2, while the
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