Brief Communication abstract
Nature Cell Biology 4, 993 - 997 (2002)
Published online: 25 November 2002 | doi:10.1038/ncb884
DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1
Oscar Fernandez-Capetillo1, Hua-Tang Chen1, Arkady Celeste1, Irene Ward2, Peter J. Romanienko3, Julio C. Morales4, Kazuhito Naka5, Zhenfang Xia4, R. Daniel Camerini-Otero3, Noboru Motoyama5, Phillip B. Carpenter4, William M. Bonner6, Junjie Chen2 & André Nussenzweig1
Activation of the ataxia telangiectasia mutated (ATM) kinase triggers diverse cellular responses to ionizing radiation (IR), including the initiation of cell cycle checkpoints1. Histone H2AX, p53 binding-protein 1 (53BP1) and Chk2 are targets of ATM-mediated phosphorylation2, 3, 4, 5, but little is known about their roles in signalling the presence of DNA damage. Here, we show that mice lacking either H2AX or 53BP1, but not Chk2, manifest a G2–M checkpoint defect close to that observed in ATM-/- cells after exposure to low, but not high, doses of IR. Moreover, H2AX regulates the ability of 53BP1 to efficiently accumulate into IR-induced foci. We propose that at threshold levels of DNA damage, H2AX-mediated concentration of 53BP1 at double-strand breaks is essential for the amplification of signals that might otherwise be insufficient to prevent entry of damaged cells into mitosis.
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Division of Oncology Research, Mayo Clinic, 200 First Street, S. W., Rochester MN 55905, USA
- Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
- Department of Biochemistry and Molecular Biology, Univeristy of Texas Health Sciences Center, Houston, TX 77030, USA
- Department of Geriatric Research, National Institute for Longevity Sciences (NILS), 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan
- Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Correspondence to: André Nussenzweig1 e-mail: andre_nussenzweig@nih.gov
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