Abstract 107: Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair

Abstract

Abstract γ-H2AX, the serine 139-phosphorylated form of the histone protein H2AX, is a marker of activation of the DNA damage machinery and is often overexpressed in many malignancies. Although γ-H2AX deregulation in cancer has previously been reported, the relevant molecular functions during carcinogenesis as well as its relationship with other histone modifications are still largely unknown. In the present study, we found that the histone methyltransferase Suppressor of Variegation 3-9 Homolog 2 (SUV39H2) methylated lysine 134 on histone H2AX, which is located in a unique portion of H2AX among the histone H2A family. When lysine 134 of histone H2AX was substituted to alanine, the amount of γ-H2AX production was significantly abolished. We also found lower γ-H2AX activity after introduction of the double-strand breakage in Suv39h2-double null cells or when SUV39H2 was knocked down. Concordantly, tissue microarray analysis of clinical lung tissues demonstrated a significantly positive correlation between K134-methylated H2AX and γ-H2AX levels. Furthermore, introduction of K134-substituted histone H2AX enhanced radio- and chemo-sensitivity of cancer cells, implying a critical role of methylation on the regulation of γ-H2AX production and the DNA repair pathways in cancer cells. This is the first report describing the functions of methylation on histone H2AX and its important role in the regulation of γ-H2AX production in cancer. Citation Format: Ryuji Hamamoto, Kenbun Sone, Yusuka Nakamura. Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 107. doi:10.1158/1538-7445.AM2015-107