Biology Reference
In-Depth Information
the chromatin was sufficient to activate ATM and the DDR without the need to
create DSBs.
57
Further, deletion of the histone H1 linker protein, which leads
to global decompaction, significantly amplified the DDR and increased DNA
repair.
58
Similarly, deletion of either the chromatin structural protein
HMGN1
59
or the Tip60 acetyltransferase, which acetylates chromatin and
ATM,
60
impairs ATM activation. Together, this work indicates that the unique
architecture of the chromatin adjacent to DSBs can have a profound impact on
the efficiency of ATM activation.
III. The Tip60 Acetyltransferase
The previous section outlined the evidence for a link between ATM acti-
vation and chromatin structure. Here, we review the evidence that a
chromatin-modifying enzyme, the Tip60 acetyltransferase, plays a central role
in linking the detection of DSBs to the activation of the ATM kinase.
A. Tip60 Is a Ubiquitously Expressed Acetyltransferase
The Tip60 (KAT5) acetyltransferase plays an essential role in a wide range
of signaling pathways, including transcriptional regulation, steroid receptor
function, chromatin remodeling, histone acetylation, DNA repair, and mainte-
nance of stem cell function.
61-63
Tip60 acetylates the
e
-amino groups of lysine
residues on both histone and nonhistone proteins,
63,64
including histones H2A
and H4,
65-68
the androgen receptor,
69
p53,
70,71
enzymes involved in glucose
metabolism,
72
the ATM kinase,
32,60,51,73
and many others.
61,72
Protein acetyla-
tion by Tip60 can directly impact protein function, including regulating p53's
apoptotic function
70,71
or activating ATM's kinase activity.
60
Tip60, like most
acetyltransferases, has low sequence specificity for protein acetylation, and can
promiscuously acetylate many proteins
in vitro
. However, Tip60 interacts
specifically with several protein complexes, and it is these protein-binding
partners that target Tip60 to specific substrates to promote their acetylation.
61,63
Further, Tip60 is a highly connected ''hub'' protein which interacts with multi-
ple proteins in complex regulatory pathways.
74
Consequently, inactivation of
Tip60 is embryonic lethal in mice,
75
underscoring the central role of Tip60 in
regulating cellular pathways required for both development andmaintenance of
cell viability.
B. Tip60 and Cancer
Although Tip60 functions as an acetyltransferase in diverse signaling sys-
tems, here we focus on its critical role in DNA repair. Tip60 is required to
maintain genomic integrity and regulate DSB repair in both mammalian and
yeast cells.
60,67,76
Loss of Tip60 function leads to increased sensitivity to
