Biology Reference
In-Depth Information
dynamic regulation of histone methylation is a key function of the DDR, and
lend support to the idea that H3K9 methylation may be increased at DSBs.
Additional studies will be required to determine if H3K9me3 levels are altered
at DSBs and to identify the specific methyltransferases involved in this process.
Further, the manner in which potential H3K9 methyltransferases are recruited
to DSBs, including the role of key DDR proteins such as H2AX, ATM, and
mdc1 in this process, remains to be determined.
C. A Special Role for Heterochromatin in
ATM Function?
H3K9me3 is predominantly located in the heterochromatin, where it is
binds to HP1 proteins. It is therefore of interest to consider how the binding of
H3K9me3 to HP1 may impact the ability of Tip60 to associate with the same
modification at DSBs.
Chromatin can be broadly divided into two types of structures. Euchroma-
tin represents open, gene-rich, transcriptionally active regions containing his-
tones, which are highly acetylated and are methylated on lysines 4 and 36 of
histone H3.
105,107
In contrast, heterochromatin, which constitutes 15-25% of
mammalian chromatin, represents condensed regions with low gene density
but high levels of repetitive sequences.
121,127
Heterochromatin also has low
levels of histone acetylation but high levels of histone H3 methylated on lysines
9 and 36.
105,121,123,128
Heterochromatin is maintained in this repressed state
through binding of specific heterochromatin-binding proteins, including
HP1
a
, HP1
b
, and HP1
g
, which bind directly to H3K9me2/3.
129,130
This pro-
motes the recruitment of other repressive factors, including methyltransferases
and histone deacetylase, which function together to promote silencing.
131,132
The high density of H3K9me3 within heterochromatin suggests that Tip60 may
be preferentially activated by DSBs generated within heterochromatin, which
would be consistent with reports that DSB repair in heterochromatin requires
ATM.
8
However, as discussed in the previous section, there is no evidence to
support the idea that ATM is only activated within specific chromatin domains.
The majority of the H3K9me3 in heterochromatin is associated with HP1.
In this situation, HP1 and Tip60 may compete for binding to H3K9me3, with
the potential that occupation of H3K9me3 sites by HP1 may preclude Tip60
binding and therefore negatively impact the DDR within heterochromatin.
Recent work has pointed to a potential mechanism for removing HP1 from the
chromatin at DSBs. This work demonstrated that DNA damage leads to the
phosphorylation of the chromodomain of HP1
b
by the CKII kinase.
133
Phos-
phorylation of HP1's chromodomain blocks the binding of HP1 to H3K9me3,
leading to the rapid release of HP1
b
from the chromatin.
51,133
This suggested a
simple mechanism in which DNA damage leads to the rapid phosphorylation
