Biology Reference
In-Depth Information
process is mediated by the MRN complex. In addition, determining if
H3K9me3 levels are increased at DSB and identifying the methyltransferase
involved are of primary importance. Finally, comparing ATM activation by
DSBs in heterochromatin and euchromatin will provide key information con-
cerning the role of reorganization of heterochromatin in the DDR response.
Following the reorganization of the chromatin, the ATM-Tip60 complex
is targeted to the chromatin through interaction with the MRN (
Fig. 1
).
This promotes interaction between Tip60's chromodomain and H3K9me3 on
adjacent nucleosomes, activating Tip60's acetyltransferase activity. Tip60 then
acetylates the PRD domain of ATM, promoting activation of ATM's kinase, a
process which also requires input from the MRN complex. Subsequently, ATM
undergoes autophosphorylation on multiple sites, promoting conversion from
the inactive dimer to the fully active monomeric form. As a significant fraction
of active ATM is mobile within the nucleoplasm, ATM acetylation may also
function to maintain ATM in the fully active, monomeric form, preventing
inactivation of ATM by phosphatases and HDACs. The continued exploration
of the complexities of ATM regulation will provide new insights into the
molecular events that occur on the chromatin in response to DSBs.
V. Conclusions and Implications for Cancer Therapy
Tip60 functions in many chromatin-dependent transactions, including
DSB repair, transcription, and regulation of the androgen receptor. The bind-
ing of Tip60's chromodomain to H3K9me3 may therefore be a common
mechanism to regulate Tip60 activity, indicating that the chromodomain is
the key transducer of epigenetic information on gene promoters regulated by
Tip60. Further, Tip60 is known to be inactivated in breast
82
and other can-
cers.
78-81
Loss of Tip60 would be predicted to impact ATM activation, leading
to impaired DSB repair and increasing the risk of a mutagenic event. Further,
as Tip60 activation relies on H3K9me3, alterations in global histone methyla-
tion patterns in tumor cells may impact Tip60 activity and its ability to regulate
DNA repair. In fact, studies have demonstrated altered or decreased levels of
H3K9me2/3 in prostate, pancreatic, lung, breast, and other cancers.
139-144
Further, genetic inactivation of several histone methyltransferases, including
Dot1, Suv4-20h, and the H3K9 methyltransferases Suv39h1 and Suv39h2,
leads to aberrant histone methylation, genomic instability, checkpoint activa-
tion, and aberrant DNA repair.
113,145-148
Taken together, these studies indicate
that alterations in the global levels of histone methylation, including changes in
H3K9me3 levels, can lead to increased genomic instability and may be a
contributing factor to the etiology and progression of cancer. In particular,
reduced levels of H3K9me3 in tumor cells may provide a mechanism for
