Letter abstract
Nature Cell Biology 8, 870 - 876 (2006)
Published online: 23 July 2006 | doi:10.1038/ncb1446
Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway
Yael Ziv1, Dana Bielopolski1, Yaron Galanty1, Claudia Lukas2, Yoichi Taya3, David C. Schultz4, Jiri Lukas2, Simon Bekker-Jensen2, Jiri Bartek2 & Yosef Shiloh1
The cellular DNA-damage response is a signaling network that is vigorously activated by cytotoxic DNA lesions, such as double-strand breaks (DSBs)1. The DSB response is mobilized by the nuclear protein kinase ATM, which modulates this process by phosphorylating key players in these pathways2. A long-standing question in this field is whether DSB formation affects chromatin condensation. Here, we show that DSB formation is followed by ATM-dependent chromatin relaxation. ATM's effector in this pathway is the protein KRAB-associated protein (KAP-1, also known as TIF1
, KRIP-1 or TRIM28), previously known as a corepressor of gene transcription3, 4. In response to DSB induction, KAP-1 is phosphorylated in an ATM-dependent manner on Ser 824. KAP-1 is phosphorylated exclusively at the damage sites, from which phosphorylated KAP-1 spreads rapidly throughout the chromatin. Ablation of the phosphorylation site of KAP-1 leads to loss of DSB-induced chromatin decondensation and renders the cells hypersensitive to DSB-inducing agents. Knocking down KAP-1, or mimicking a constitutive phosphorylation of this protein, leads to constitutive chromatin relaxation. These results suggest that chromatin relaxation is a fundamental pathway in the DNA-damage response and identify its primary mediators.
- The David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
- Danish Cancer Society, Institute of Cancer Biology and Centre of Genotoxic Stress Research, DK-2100 Copenhagen, Denmark.
- Radiobiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.
- Case Western Reserve University, Department of Pharmacology, 10900 Euclid Avenue, Cleveland, OH 44106-4965, USA.
Correspondence to: Yael Ziv1 e-mail: yaelz@post.tau.ac.il
Correspondence to: Yosef Shiloh1 e-mail: yossih@post.tau.ac.il
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