Goodarzi Aaron A, Noon Angela T, Deckbar Dorothee, Ziv Yael, Shiloh Yosef, Löbrich Markus, Jeggo Penny A
Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK.
Mol Cell. 2008 Jul 25;31(2):167-77. doi: 10.1016/j.molcel.2008.05.017.
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 < or =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.
共济失调毛细血管扩张症突变基因（ATM）信号通路对于一部分DNA双链断裂（DSB）的修复至关重要；然而，其确切作用尚不清楚。在此，我们表明小于或等于25%的DSB修复需要ATM信号通路，并且这一比例与染色质增加相关，但与损伤复杂性无关。重要的是，我们证明异染色质DSB的修复通常比常染色质DSB更慢，并且ATM信号通路是异染色质内DSB修复所特需的。值得注意的是，转录抑制因子KAP-1（一种ATM底物）、异染色质形成因子HP1或HDAC1/2的敲低减轻了DSB修复中对ATM的需求。我们提出，ATM信号通路通过KAP-1暂时扰乱异染色质，这对于在原本致密/不灵活的染色质内进行DSB修复/加工至关重要。为此提供支持的是，ATM信号通路改变了KAP-1对富含异染色质因子的染色质的亲和力。这些数据表明，随着基因组异染色质成分的扩展，ATM信号通路对DSB修复的重要性增加。
