title: Activation of ATM depends on chromatin interactions occurring before induction of DNA damage.
abstract: Efficient and correct responses to double-stranded breaks (DSB) in chromosomal DNA are crucial for maintaining genomic stability and preventing chromosomal alterations that lead to cancer. The generation of DSB is associated with structural changes in chromatin and the activation of the protein kinase ataxia-telangiectasia mutated (ATM), a key regulator of the signalling network of the cellular response to DSB. The interrelationship between DSB-induced changes in chromatin architecture and the activation of ATM is unclear. Here we show that the nucleosome-binding protein HMGN1 modulates the interaction of ATM with chromatin both before and after DSB formation, thereby optimizing its activation. Loss of HMGN1 or ablation of its ability to bind to chromatin reduces the levels of ionizing radiation (IR)-induced ATM autophosphorylation and the activation of several ATM targets. IR treatments lead to a global increase in the acetylation of Lys 14 of histone H3 (H3K14) in an HMGN1-dependent manner and treatment of cells with histone deacetylase inhibitors bypasses the HMGN1 requirement for efficient ATM activation. Thus, by regulating the levels of histone modifications, HMGN1 affects ATM activation. Our studies identify a new mediator of ATM activation and demonstrate a direct link between the steady-state intranuclear organization of ATM and the kinetics of its activation after DNA damage.
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Gabi
authors.initials: G
authors.lastname: Gerlitz
authors.forename: Takashi
authors.initials: T
authors.lastname: Furusawa
authors.forename: Frédéric
authors.initials: F
authors.lastname: Catez
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Kyu-Seon
authors.initials: KS
authors.lastname: Oh
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Kraemer
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
mesh_terms: D000107:Acetylation / Q000528:radiation effects; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism / Q000528:radiation effects; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D042822:Genomic Instability / Q000235:genetics; D024241:HMGN1 Protein / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000528:radiation effects; D008239:Lysine / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011839:Radiation, Ionizing; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D024241:HMGN1 Protein; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D006655:Histone Deacetylases; D008239:Lysine