Kulashreshtha Mugdha, Mehta Ishita S, Kumar Pradeep, Rao Basuthkar J
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India.
Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra 400005, India UM-DAE Centre for Excellence in Basic Sciences, Biological Sciences, Kalina Campus, Santacruz (E), Mumbai, Maharashtra 400098, India.
Nucleic Acids Res. 2016 Sep 30;44(17):8272-91. doi: 10.1093/nar/gkw573. Epub 2016 Jun 30.
During DNA damage response (DDR), certain gene rich chromosome territories (CTs) relocate to newer positions within interphase nuclei and revert to their native locations following repair. Such dynamic relocation of CTs has been observed under various cellular conditions, however, the underlying mechanistic basis of the same has remained largely elusive. In this study, we aim to understand the temporal and molecular details of such crosstalk between DDR signaling and CT relocation dynamics. We demonstrate that signaling at DNA double strand breaks (DSBs) by the phosphorylated histone variant (ϒ-H2AX) is a pre-requisite for damage induced CT relocation, as cells deficient in ϒ-H2AX signaling fail to exhibit such a response. Inhibition of Rad51 or DNA Ligase IV mediated late steps of double strand break repair does not seem to abrogate CT relocation completely. Upon DNA damage, an increase in the levels of chromatin bound motor protein nuclear myosin 1 (NM1) ensues, which appears to be functionally linked to ϒ-H2AX signaling. Importantly, the motor function of NM1 is essential for its recruitment to chromatin and CT relocation following damage. Taking these observations together, we propose that early DDR sensing and signaling result in NM1 recruitment to chromosomes which in turn guides DNA damage induced CT relocation.
在DNA损伤反应（DDR）过程中，某些富含基因的染色体区域（CTs）会迁移到间期核内的新位置，并在修复后恢复到其原始位置。这种CTs的动态迁移已在各种细胞条件下被观察到，然而，其潜在的机制基础在很大程度上仍然难以捉摸。在这项研究中，我们旨在了解DDR信号与CT迁移动力学之间这种相互作用的时间和分子细节。我们证明，磷酸化组蛋白变体（ϒ-H2AX）在DNA双链断裂（DSBs）处的信号传导是损伤诱导CT迁移的先决条件，因为缺乏ϒ-H2AX信号传导的细胞无法表现出这种反应。抑制Rad51或DNA连接酶IV介导的双链断裂修复后期步骤似乎并不能完全消除CT迁移。DNA损伤后，染色质结合的运动蛋白核肌球蛋白1（NM1）水平会随之增加，这似乎在功能上与ϒ-H2AX信号传导相关。重要的是，NM1的运动功能对于其在损伤后募集到染色质和CT迁移至关重要。综合这些观察结果，我们提出早期DDR感知和信号传导会导致NM1募集到染色体上，进而指导DNA损伤诱导的CT迁移。
