Involvement of Histone H1.2 in Apoptosis Induced by DNA Double-Strand Breaks

• Published in: Cell Vol. 114; no. 6; pp. 673 - 688
• Main Authors: Konishi, Akimitsu, Shimizu, Shigeomi, Hirota, Junko, Takao, Toshifumi, Fan, Yuhong, Matsuoka, Yosuke, Zhang, Lilin, Yoneda, Yoshihiro, Fujii, Yoshitaka, Skoultchi, Arthur I., Tsujimoto, Yoshihide
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19-09-2003
• Subjects: Animals; Apoptosis - genetics; Apoptosis - radiation effects; Apoptotic Protease-Activating Factor 1; bcl-2 Homologous Antagonist-Killer Protein; Cell Nucleus - genetics; Cell Nucleus - metabolism; Cell Nucleus - radiation effects; Cytochrome c Group - genetics; DNA Damage - genetics; DNA Damage - radiation effects; Escherichia coli Proteins; Etoposide - pharmacology; Eukaryotic Cells - metabolism; Eukaryotic Cells - radiation effects; Histones - genetics; Histones - radiation effects; Humans; Intestine, Small - radiation effects; Male; Membrane Proteins - drug effects; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - radiation effects; Phosphoenolpyruvate Sugar Phosphotransferase System - drug effects; Phosphoenolpyruvate Sugar Phosphotransferase System - genetics; Protein Isoforms - genetics; Protein Isoforms - radiation effects; Proteins - genetics; Proteins - metabolism; Rats; Thymus Gland - radiation effects; Tumor Necrosis Factor-alpha - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ultraviolet Rays - adverse effects; X-Rays - adverse effects
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(03)00719-0

It is poorly understood how apoptotic signals arising from DNA damage are transmitted to mitochondria, which release apoptogenic factors into the cytoplasm that activate downstream destruction programs. Here, we identify histone H1.2 as a cytochrome c-releasing factor that appears in the cytoplasm after exposure to X-ray irradiation. While all nuclear histone H1 forms are released into the cytoplasm in a p53-dependent manner after irradiation, only H1.2, but not other H1 forms, induced cytochrome c release from isolated mitochondria in a Bak-dependent manner. Reducing H1.2 expression enhanced cellular resistance to apoptosis induced by X-ray irradiation or etoposide, but not that induced by other stimuli including TNF-α and UV irradiation. H1.2-deficient mice exhibited increased cellular resistance in thymocytes and the small intestine to X-ray-induced apoptosis. These results indicate that histone H1.2 plays an important role in transmitting apoptotic signals from the nucleus to the mitochondria following DNA double-strand breaks.