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and release of HP1
b
from H3K9me3 at DSBs.
51,133
This mechanism would
therefore generate domains of H3K9me3 which would then be available to
interact with Tip60's chromodomain. However, this simple idea is more com-
plex than originally thought. A recent study reported that HP1 proteins are
actively recruited to sites of DNA damage, and that this recruitment was
independent of their ability to associate with H3K9me3.
134,135
Instead, HP1
proteins were localized to the damaged chromatin via their chromoshadow
domain. Indeed, the original work detailing release of HP1 from the chromatin
after damage noted that the ejected HP1 rebound to H3K9me3 at later
times.
133
The dynamics of HP1 binding to H3K9me3 are therefore complex
and subject to regulation at multiple levels.
Recent work indicates that, in addition to HP1, ATM can phosphorylate
kap1, a previously identified heterochromatin-binding protein.
136
Phosphory-
lation of kap1 by ATM is required for global relaxation of chromatin struc-
ture
136
and for DSB repair within heterochromatin.
8,137
DSB repair was
demonstrably slower in heterochromatic regions, and unrepaired DSBs per-
sisted at heterochromatin boundaries in the absence of either ATM or kap-1
phosphorylation
8,137
(reviewed in Ref.
7
). The key conclusion from these
studies is that phosphorylation of kap-1 by ATM opens up the heterochromatin
structure and that this process promotes both access to and repair of DSBs.
Interestingly, it is yet not clear how phosphorylation of kap1 impacts hetero-
chromatin structure as phospho-kap1 remains associated with the chromatin.
8
Phosphorylation may alter kap1 association with other repressive proteins,
such as HDACs and methyltransferases,
131,132,138
shifting the balance toward
a less repressed chromatin structure. However, given that two sets of
heterochromatin-binding proteins, the HP1 family and the kap1 repressor,
are phosphorylated in response to DNA damage and are either released or
relocated on the chromatin,
8,51,133,134,136,137
it is clear that reorganization of
heterochromatin and changes in accessibility to H3K9me3 are fundamental
aspects of the cells' immediate response to DSBs. Reorganization of the
chromatin and, in particular, altering the interactions between HP1,
H3K9me3, and kap1, may introduce flexibility into the chromatin and increase
access of Tip60 to preexisting H3K9me3, as well as promoting
de novo
meth-
ylation of H3K9me3. Probing ATM activation and function within clearly
defined heterochromatin domains will continue to provide key insights into
this process.
D. Chromatin Dynamics and ATM Activation
Figure 1
outlines a general scheme for activation of ATM by Tip60, taking
into account contributions from HP1, the MRN complex, H3K9me3, and the
Tip60 acetyltransferase. Generation of DSBs leads to the rapid recruitment of
the MRN complex to the break. In addition, HP1 associated with adjacent
