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. Histone H2AX deficiency decreases genomic stability and increases tumor susceptibility of normal cells and tissues. However, the role of histone H2AX phosphorylation in malignant transformation and cancer development is not totally clear. Herein, we found that ribosomal S6 kinase 2 (RSK2) directly phosphorylates histone H2AX at Ser139 and also at a newly discovered site, Ser16. Epidermal growth factor (EGF)-induced phosphorylation of histone H2AX at both sites was decreased in RSK2 knockout cells. Phosphorylated RSK2 and histone H2AX colocalized in the nucleus following EGF treatment, and the phosphorylation of histone H2AX by RSK2 enhanced the stability of histone 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 wild-type H2AX compared with H2AX knockout (H2AX-/-) cells. EGF-associated AP-1 transactivation activity was dramatically lower in H2AX-/- cells overexpressing wild-type H2AX than 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.
Highlights
Histone H2AX, a variant of histone H2A that is ubiquitously expressed throughout the genome, has been designated as the histone guardian of the genome [1]
We reported previously that ultraviolet A (UVA) irradiation induces histone H2AX phosphorylation that is mediated by c-Jun N-terminal kinases (JNK), and the JNKs/ H2AX pathway is associated with the induction of apoptosis [12]
The results indicated that the phospho-H2AX (Ser16) antibody did not recognize any other histones in H2AXÀ/À
Summary
Histone H2AX, a variant of histone H2A that is ubiquitously expressed throughout the genome, has been designated as the histone guardian of the genome [1]. We reported previously that ultraviolet A (UVA) irradiation induces histone H2AX phosphorylation that is mediated by c-Jun N-terminal kinases (JNK), and the JNKs/ H2AX pathway is associated with the induction of apoptosis [12]. We found that T-cell–originated protein kinase (TOPK) directly phosphorylates histone H2AX and is involved in arsenic-induced apoptosis of melanoma cells [13]. Histone H2AX phosphorylation is induced by various stresses, such as replication stress [9, 12, 14, 15], endogenous stress [16], ionizing radiation [17], and other agents that cause DNA damage [18], including DNA DSBs [19, 20]. The mitogen-activated protein kinases (MAPK) are a family of protein kinases that mediate distinct signaling cascades, which are targets for diverse extracellular stimuli including growth factors [24, 25]
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