Abstract 1017: Phosphorylation of histone H2AX at Ser139 and a new phosphorylation site Ser16 by RSK2 decreases H2AX ubiquitination and inhibits cell transformation

Abstract

Abstract Histone H2AX is a histone H2A variant that is ubiquitously expressed throughout the genome. It plays a key role in the cellular response to DNA damage and has been designated as the histone guardian of the genome. H2AX deficiency decreases genomic stability and increases tumor susceptibility of normal cells and tissues. However, the role of H2AX phosphorylation in malignant transformation and cancer development is not totally clear. We found that ribosomal S6 kinase 2 (RSK2) directly phosphorylates H2AX at Ser139 and also at a newly discovered site, Ser16. EGF-induced phosphorylation of H2AX at both sites was decreased in RSK2 knockout cells. Phosphorylated RSK2 and H2AX co-localized in the nucleus following EGF treatment and the phosphorylation of H2AX by RSK2 enhanced the stability of H2AX and prevented cell transformation induced by EGF. RSK2 and DNA-PK, but not ATM or ATR, are required for EGF-induced phosphorylation of H2AX at Ser139. However, only RSK2 is required for phosphorylation of H2AX at Ser16. Phosphorylation of histone H3 was suppressed in cells expressing wildtype H2AX compared with H2AX knockout (H2AX-/-) cells. EGF-associated AP-1 transactivation activity was dramatically lower in H2AX-/- cells overexpressing wildtype H2AX compared with H2AX-/- cells expressing mutant H2AX-AA. Thus, the RSK2/H2AX signaling pathway negatively regulates the RSK2/histone H3 pathway and therefore maintains normal cell proliferation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1017. doi:10.1158/1538-7445.AM2011-1017