Biology Reference
In-Depth Information
HP1
p
HP1
Me
Me
[2] Recruitment:
MRN
MRN
ATM/Tip60
H3K9me3?
HP1
[1] Chromatin reorganization:
HP1 phosphorylation
HP1 reorganization (?)
Ac
Tip60
[3] Tip60 activation:
ATM acetylation
Kinase activation
Me
Me
MRN
Ac
P
P
P
Tip60
[4] ATM activation:
Autophosphorylation
Me
Me
MRN
Ac
P
P
P
[5] ATM activation:
Dimer
Ac
P
P
P
monomer
F
IG
.1.
A mechanism for ATM activation
. [1] Following DSB production, MRN is recruited to
DSB. [2] HP1 proteins are released from H3K9me3, and either retained on the chromatin or
released to the nucleoplasm by a process involving phosphorylation of HP1 by the CK2 kinase.
133
It
is not known whether MRN participates in this process. Inducible methylation of H3K9 by
unknown methyltransferases may also occur at this point. [3] The inactive ATM-Tip60 complex is
recruited to the DSB by MRN, facilitating interactions between Tip60's chromodomain and
H3K9me3. This activates Tip60 acetyltransferase activity, leading to acetylation of the PRD of
ATM. [4] Interaction between MRN and ATM, in combination with acetylation of ATM by Tip60,
activates ATM's kinase activity, promoting autophosphorylation of ATM. [5] Separation of inactive
ATM dimers into the fully active ATM monomers. Me, methylation; Ac, acetylation; P, phosphor-
ylation; MRN, Mre11-Rad50-nbs1; HP1, heterochromatin-binding protein.
H3K9me3 is phosphorylated and either ejected from the chromatin or relo-
cated to nearby chromatin locations. This primary reorganization of the local
chromatin architecture will create domains of H3K9me3 free of associated
HP1. In addition, there is the potential that DSBs also lead to the inducible
methylation of H3K9 through recruitment of specific methyltransferases,
which may be particularly important for chromatin regions which normally
lack this modification, such as euchromatin. However, these early steps in the
DSB repair response are poorly characterized and further work will be required
to unravel the complexity of these issues. In particular, it is important to resolve
the issue of how HP1 binding is altered during repair, and to determine if this
