title: Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway.
abstract: The cellular DNA-damage response is a signaling network that is vigorously activated by cytotoxic DNA lesions, such as double-strand breaks (DSBs). The DSB response is mobilized by the nuclear protein kinase ATM, which modulates this process by phosphorylating key players in these pathways. 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 TIF1beta, KRIP-1 or TRIM28), previously known as a corepressor of gene transcription. 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.
authors.affiliation: 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. yaelz@post.tau.ac.il
authors.forename: Yael
authors.initials: Y
authors.lastname: Ziv
authors.forename: Dana
authors.initials: D
authors.lastname: Bielopolski
authors.forename: Yaron
authors.initials: Y
authors.lastname: Galanty
authors.forename: Claudia
authors.initials: C
authors.lastname: Lukas
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: David C
authors.initials: DC
authors.lastname: Schultz
authors.forename: Jiri
authors.initials: J
authors.lastname: Lukas
authors.forename: Simon
authors.initials: S
authors.lastname: Bekker-Jensen
authors.forename: Jiri
authors.initials: J
authors.lastname: Bartek
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000076183:Tripartite Motif-Containing Protein 28; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009353:Zinostatin / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D009353:Zinostatin; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases