Article abstract
Nature Cell Biology 11, 172 - 182 (2009)
Published online: 18 January 2009 | doi:10.1038/ncb1831
CHD8 suppresses p53-mediated apoptosis through histone H1 recruitment during early embryogenesis
Masaaki Nishiyama1,2, Kiyotaka Oshikawa1,2, Yu-ichi Tsukada1,2, Tadashi Nakagawa1,2, Shun-ichiro Iemura3, Tohru Natsume3, Yuhong Fan4,5, Akira Kikuchi6, Arthur I. Skoultchi4 & Keiichi I. Nakayama1,2
Abstract
The chromodomain helicase DNA-binding (CHD) family of enzymes is thought to regulate gene expression, but their role in the regulation of specific genes has been unclear. Here we show that CHD8 is expressed at a high level during early embryogenesis and prevents apoptosis mediated by the tumour suppressor protein p53. CHD8 was found to bind to p53 and to suppress its transactivation activity. CHD8 promoted the association of p53 and histone H1, forming a trimeric complex on chromatin that was required for inhibition of p53-dependent transactivation and apoptosis. Depletion of CHD8 or histone H1 resulted in p53 activation and apoptosis. Furthermore, Chd8-/- mice died early during embryogenesis, manifesting widespread apoptosis, whereas deletion of p53 ameliorated this developmental arrest. These observations reveal a mode of p53 regulation mediated by CHD8, which may set a threshold for induction of apoptosis during early embryogenesis by counteracting p53 function through recruitment of histone H1.
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
- CREST, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan.
- National Institute of Advanced Industrial Science and Technology (AIST), Biological Information Research Center (JBIRC), Kohtoh-ku, Tokyo 135-0064, Japan.
- Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
- School of Biology and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, IBB 2313, 315 Ferst Drive, Atlanta, GA 30332-0363, USA.
- Department of Biochemistry, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Correspondence to: Keiichi I. Nakayama1,2 e-mail: nakayak1@bioreg.kyushu-u.ac.jp
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