Harding Shane M, Boiarsky Jonathan A, Greenberg Roger A
Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Departments of Cancer Biology and Pathology, Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104, USA.
Cell Rep. 2015 Oct 13;13(2):251-9. doi: 10.1016/j.celrep.2015.08.085. Epub 2015 Oct 1.
Resolution of DNA double-strand breaks (DSBs) is essential for the suppression of genome instability. DSB repair in transcriptionally active genomic regions represents a unique challenge that is associated with ataxia telangiectasia mutated (ATM) kinase-mediated transcriptional silencing. Despite emerging insights into the underlying mechanisms, how DSB silencing connects to DNA repair remains undefined. We observe that silencing within the rDNA depends on persistent DSBs. Non-homologous end-joining was the predominant mode of DSB repair allowing transcription to resume. ATM-dependent rDNA silencing in the presence of persistent DSBs led to the large-scale reorganization of nucleolar architecture, with movement of damaged chromatin to nucleolar cap regions. These findings identify ATM-dependent temporal and spatial control of DNA repair and provide insights into how communication between DSB signaling and ongoing transcription promotes genome integrity.
DNA双链断裂（DSB）的修复对于抑制基因组不稳定至关重要。转录活跃基因组区域中的DSB修复是一项独特的挑战，与共济失调毛细血管扩张症突变（ATM）激酶介导的转录沉默相关。尽管对潜在机制有了新的认识，但DSB沉默与DNA修复之间的联系仍不明确。我们观察到核糖体DNA（rDNA）内的沉默取决于持续性DSB。非同源末端连接是DSB修复的主要模式，可使转录恢复。在存在持续性DSB的情况下，ATM依赖性rDNA沉默导致核仁结构的大规模重组，受损染色质向核仁帽区域移动。这些发现确定了ATM对DNA修复的时空控制，并为DSB信号传导与正在进行的转录之间的通讯如何促进基因组完整性提供了见解。
