ATM Signaling Facilitates Repair of DNA Double-Strand Breaks Associated with Heterochromatin

Aaron A. Goodarzi, Angela T. Noon, Dorothee Deckbar, Yael Ziv, Yosef Shiloh, Markus Löbrich, Penny A. Jeggo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

711 Scopus citations

Abstract

Ataxia Telangiectasia Mutated (ATM) signaling is essential for the repair of a subset of DNA double-strand breaks (DSBs); however, its precise role is unclear. Here, we show that ≤25% of DSBs require ATM signaling for repair, and this percentage correlates with increased chromatin but not damage complexity. Importantly, we demonstrate that heterochromatic DSBs are generally repaired more slowly than euchromatic DSBs, and ATM signaling is specifically required for DSB repair within heterochromatin. Significantly, knockdown of the transcriptional repressor KAP-1, an ATM substrate, or the heterochromatin-building factors HP1 or HDAC1/2 alleviates the requirement for ATM in DSB repair. We propose that ATM signaling temporarily perturbs heterochromatin via KAP-1, which is critical for DSB repair/processing within otherwise compacted/inflexible chromatin. In support of this, ATM signaling alters KAP-1 affinity for chromatin enriched for heterochromatic factors. These data suggest that the importance of ATM signaling for DSB repair increases as the heterochromatic component of a genome expands.

Original languageEnglish
Pages (from-to)167-177
Number of pages11
JournalMolecular Cell
Volume31
Issue number2
DOIs
StatePublished - 25 Jul 2008

Funding

FundersFunder number
Forschungszentrum Karlsruhe02S8135, 02S8355
International Association for Cancer Research
Leukaemia Research Fund
Wilhelm Sander-Stiftung2003.114.1/3
Medical Research CouncilG0500897
European CommissionLSHG-CT-2005-512113, FI6R-CT-2003-508842
Deutsche ForschungsgemeinschaftLO 677/4-1/2
Bundesministerium für Bildung und Forschung
Alberta Heritage Foundation for Medical Research
Department of Health, Australian Government

    Keywords

    • DNA
    • SIGNALING

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