Abstract B40: Histone H3 methylation couples DNA damage detection to activation of the Tip60 tumor suppressor

Abstract

Abstract Cancer is a heterogeneous disease which arises primarily from the accumulation of mutations and deletions in the cells DNA. However, recent work has implicated both DNA methylation and histone modifications in the etiology and progression of cancer. For example, abnormal patterns of histone methylation have been identified in breast cancer, raising the possibility that altered patterns of histone methylation can be exploited both as a biomarker to monitor disease status and as a novel therapeutic target. Here, we report on a novel role for histone methylation in regulating the ability of the Tip60 acetyltransferase to repair DNA double strand breaks (DSBs). Tip60 is a haplo-insufficient tumor suppressor, and loss of heterozygosity at the Tip60 locus and reduced levels of nuclear Tip60 have been detected in both breast and prostate cancer. Tip60 is an acetyltransferase, and can acetylate several DNA repair proteins implicated in breast cancer, including myc, p53 and ATM. Previously, we demonstrated that Tip60 acetylates and activates the ATM protein, a key component of the cells DSB repair mechanism. Here, we demonstrate that methylation of histones creates docking sites for the recruitment of the Tip60 DNA repair complex to sites of DNA damage. Further, interaction between Tip60 and methylated histones serves to specifically activate Tip60'fs acetyltransferase activity at DSBs. Reduction in histone methylation levels compromises Tip60 activation, leading to reduced DNA repair and increased genomic instability. These results indicate that the level and distribution of specific histone methylation marks across the chromatin is a critical determinant of cells ability to repair and survive DNA damage. Thus histone methylation may regulate the genomic stability of cells and their intrinsic sensitivity to agents, including radio- and chemo-therapy, which directly damage DNA. Altered histone methylation associated with breast cancer may therefore contribute to both genomic instability and to resistance to therapy. Finally, since histone methylation is reversible, the enzymes controlling histone methylation represent an exciting new target for therapy in breast cancer. Citation Information: Cancer Res 2009;69(23 Suppl):B40.