Mechanistic Links Between ATM and Histone Methylation Codes During DNA Repair - Progress in Molecular Biology - page 265

IR 32,60,67,51,77 and the accumulation of multiple chromosomal aberrations. 51
Analysis of several tumor types indicates that Tip60 expression levels are
altered in prostate, breast, and colorectal cancer. 78-81 In particular, Tip60
functions as a haplo-insufficient tumor suppressor in breast cancer, with re-
duced levels of nuclear Tip60 frequently identified in breast tumor samples. 82
The observation that Tip60 protein levels are reduced in tumors is consistent
with the idea that Tip60 is an essential hub gene, regulating many distinct
pathways in the cell. Reduction in the levels of Tip60 protein, rather than
mutational inactivation or deletion, would allow tumor cells to limit Tip60
activity directed toward the DDR while maintaining essential transcriptional
and regulatory functions. This, in turn, would allow tumors to maintain the
elevated levels of genomic instability associated with tumor progression.
Although the mechanism by which Tip60 levels are reduced in tumors is not
known, methylation of the Tip60 promoter or expression of microRNAs target-
ing Tip60 expression is likely to dominate in tumor cells. Continued studies in
this area are therefore likely to yield important information on the role of Tip60
in tumorigenesis.
Thus, a key function of Tip60 is to protect cells from genomic instability by
regulating the DDR and suppressing potentially transforming events that lead
to cancer. We now know that Tip60 controls genomic stability through its ability
to regulate two key components of the DDR—chromatin remodeling at DSBs
by the NuA4-Tip60 complex and acetylation and activation of the ATM kinase.
NuA4 is a multi-subunit chromatin-remodeling complex containing p400, a
large motor ATPase, and Tip60, an acetyltransferase activity. 83 Several subunits
of NuA4, including p400 and Tip60, are recruited to DSBs in both yeast 84
and mammalian cells. 5,77,85 The recruitment of NuA4 to the chromatin at
DSBs leads to increased acetylation of histones H2AX and H4 66,77,84,86,87 and
a reduction in the stability of nucleosomes at DSBs. 5,77,85 This allows the
NuA4-Tip60 complex to create open, mobile chromatin domains that facilitate
the recruitment and loading of DDR proteins (including brca1 and 53BP1)
onto the chromatin at DSBs (reviewed in Refs. 5,77,85 ). Chromatin acetylation
by the NuA4-Tip60 complex is required for DSB repair; however, this review
focuses on the ability of Tip60 to directly acetylate and activate the ATM kinase.
C. Tip60 and ATM Acetylation
The ability of Tip60 to directly acetylate the ATM kinase represents a new
type of mechanism for kinase regulation. Previous work had shown that Tip60's
acetyltransferase activity was essential for the DDR. 32,60,67,51,77 Recently, it was
shown that Tip60's acetyltransferase activity was increased in response to IR
and that this led to direct acetylation of ATM by Tip60, 60 a finding confirmed by
several other groups. 59,88,89 Further, inactivation of Tip60 inhibited both ATM
acetylation and activation of ATM's kinase activity. 6,60 Subsequently, a single