Biology Reference
In-Depth Information
contribute to the creation of the fully active ATM kinase in response to DSBs in
cells. However, it should be noted that ATM activation in response to DNA
damage is complex and subject to regulation at multiple levels. The contribu-
tion of other factors, including the degree of chromatin compaction at breaks,
58
chromatin structural proteins such as HMGN1,
59
and the recently described
ATM regulatory protein ATMIN,
55,56
are all likely to make important contri-
butions. In addition, ATM activation can occur independently of DSB produc-
tion. For example, direct oxidation of ATM during oxidative stress activates
ATM by a mechanism which was independent of both MRN and DSBs.
117
Further, ATM activation is implicated in signaling by retinoic acid
118
and
insulin signaling,
119,120
underscoring the diverse range of non-DNA damage
mechanisms which can mediate full activation of ATM. Unraveling the com-
plexity of ATM activation will continue to provide insight into the regulation of
this pivotal protein kinase.
IV. H3K9me3 and DDR
The critical role for the interaction between H3K9me3 and Tip60 in
regulating DSBs raises several intriguing questions about the role of
H3K9me3 in the overall DDR. Foremost among these is to determine how
the chromodomain of Tip60 can locate and interact with H3K9me3 at DSBs.
Two broad mechanisms can be proposed. First, Tip60 may utilize H3K9me3,
which is already present on nucleosomes adjacent to the DSB. Alternatively,
nucleosomes at the break may undergo
de novo
methylation of H3K9 to create
H3K9me3 interaction sites for Tip60. Here, we discuss the evidence for these
two alternate mechanisms.
A. Tip60 Activation by Preexisting H3K9me3
If Tip60 utilizes preexisting H3K9me3 for activation of its acetyltransferase
activity, this would require that H3K9me3 be evenly distributed across the
entire chromatin to ensure correct Tip60 activation. Otherwise, chromatin
domains lacking significant levels of H3K9me3 would fail to activate Tip60
and consequently fail to activate ATM's kinase activity. In fact, genome-wide
ChIP studies indicate that H3K9me3 is predominantly located in the com-
pacted, gene-poor heterochromatic regions of the chromatin,
104,105,121
where it
is associated with members of the HP1 protein family.
122
However, H3K9me3
has also been detected in non-heterochromatic regions,
123
indicating that
H3K9me3 is not entirely restricted to heterochromatic regions. However,
despite the presence of H3K9me3 in non-heterochromatin domains, there
are likely to be large chromatin domains (megabases in size) which lack
detectable H3K9me3. In this case, DSBs generated in regions lacking
