TY - JOUR
T1 - Involvement of histone H1.2 in apoptosis induced by DNA double-strand breaks
AU - Konishi, Akimitsu
AU - Shimizu, Shigeomi
AU - Hirota, Junko
AU - Takao, Toshifumi
AU - Fan, Yuhong
AU - Matsuoka, Yosuke
AU - Zhang, Lilin
AU - Yoneda, Yoshihiro
AU - Fujii, Yoshitaka
AU - Skoultchi, Arthur I.
AU - Tsujimoto, Yoshihide
N1 - Funding Information:
We are grateful to Dr. C.B. Thompson for providing Bak −/− mice. We also thank Dr. S.W. Lowe for providing E1A and Ras plasmids and Dr. X. Wang for Apaf-1 +/+ and −/− MEFs. This study was supported in part by a grant for Scientific Research on Priority Areas, a grant for Center of Excellence Research, a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan, and by Special Coordination Funds for Promoting Science and Technology from the Science and Technology Agency of Japan.
PY - 2003/9/19
Y1 - 2003/9/19
N2 - 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.
AB - 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.
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U2 - 10.1016/S0092-8674(03)00719-0
DO - 10.1016/S0092-8674(03)00719-0
M3 - Article
C2 - 14505568
AN - SCOPUS:10744233286
SN - 0092-8674
VL - 114
SP - 673
EP - 688
JO - Cell
JF - Cell
IS - 6
ER -