Activation of ATM depends on chromatin interactions occurring before induction of DNA damage

Yong Chul Kim, Gabi Gerlitz, Takashi Furusawa, Frédéric Catez, Andre Nussenzweig, Kyu Seon Oh, Kenneth H. Kraemer, Yosef Shiloh, Michael Bustin

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)92-96
Number of pages5
JournalNature Cell Biology
Volume11
Issue number1
DOIs
StatePublished - 2009

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