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limiting ATM activity and allowing the tumor to maintain or tolerate increased
genomic instability. Further, it implies that DNA damage occurring in regions of
low/absent H3K9me3 may be repaired with lower efficiency than in regions
of high H3K9me3 density. Overall, this indicates that histone methylation
patterns may play a key role in controlling both genomic stability and the
sensitivity of tumor cells to DNA damage.
Finally, histone methylation provides the potential for novel therapeutic
strategies to be employed against tumors. For example, tumors with reduced
levels of H3K9me3 and impaired ATM activation may be more sensitive to
specific types of chemotherapy or to radiotherapy. Epigenetic therapies aimed
at inhibiting H3K9 methyltransferases (to decrease H3K9me3) or H3K9me3
demethylases (to increase H3K9 methylation) may be effective at sensitizing
tumor cells to radiation therapy and/or protecting normal tissue from radiation
damage. Understanding the dynamics of histone methylation, and the crucial
role that epigenetic markers play inDSB repair and ATMactivation, will provide
new therapeutic approaches for the prevention and treatment of cancer.
Acknowledgments
We thank A. D'Andrea and members of the Price laboratory for the critical discussions and
reading of the manuscript. This work was supported by grants from the NCI (CA64585 and
CA93602) and the DOD Breast Cancer Program to B. D. P.
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