Mechanistic Links Between ATM and Histone Methylation Codes During DNA Repair - Progress in Molecular Biology - page 267

substrate proteins. Continued studies on understanding how acetylation of
ATM's PRD regulates ATM's kinase activity, including structural studies, will
provide insight into the regulation of this unique kinase.

D. Activation of Tip60 by DSBs
This leads to the key question for understanding how Tip60 regulates
ATM—how is the acetyltransferase activity of Tip60 regulated in response to
DSBs? One potential mechanism is through posttranslational modification of
Tip60. Tip60 is known to undergo both phosphorylation 99 and autoacetyla-
tion 100 in response to DNA damage. However, studies in our laboratory (B.D.
Price, unpublished observations) indicate that changes in the posttranslational
modification of Tip60 are not involved in the upregulation of Tip60's acetyl-
transferase activity. However, recent work uncovered a key role for the chro-
modomain of Tip60 in regulating Tip60's acetyltransferase activity. 51
Chromodomains are unique protein domains containing conserved hydro-
phobic amino acids that specifically interact with methylated lysine residues. 101
Lysine methylation is a common posttranslational modification of histones in
which the e -amino group of lysine is either mono-, di- or trimethylated, 102,103
with each methylation state encoding specific functional information. For
example, methylation of histone H3 on lysines 9 or 27 and histone H4 on lysine
20 is associated with the inactive heterochromatin, 103-105 whereas methylation
of histone H3 on lysines 4 and 36 is associated with transcriptionally active
genes. 106-108 Similar to other signal transduction pathways, histone methyla-
tion is a dynamic process. A large family of lysine methyltransferases (KMTs),
which can create mono-, di-, or trimethylated lysine, has been described. 109,110
Similarly, several families of lysine demethylases, which remove one or more
methyl groups from methylated lysine residues, have been described. 111,112
Rapid changes in histone methylation have been implicated in diverse cellular
processes, including transcription, DNA replication, and DNA repair. Histone
methylation, therefore, represents a dynamic signaling system that creates
specific methylation marks for recruitment of chromatin-modifying complexes
to the chromatin.
Because Tip60 is recruited to DSBs, 60 Sun et al . proposed that this would
promote interaction between Tip60's chromodomain and methylated lysine
residues on the chromatin. 51 There is now strong evidence that Tip60's chro-
modomain interacts with a specific histone modification—histone H3 trimethy-
lated on lysine 9 (H3K9me3; Ref. 51 ). Both in vitro and in vivo analyses
indicate that binding of H3K9me3 to Tip60 functions as an allosteric regulator,
increasing the catalytic activity of Tip60. Mutations in the highly conserved
hydrophobic amino acids of Tip60's chromodomain block both binding of
H3K9me3 to Tip60 and activation of Tip60's acetyltransferase activity by
DNA damage. Corresponding experiments

in vivo demonstrated that