Nozawa Ryu-Suke, Boteva Lora, Soares Dinesh C, Naughton Catherine, Dun Alison R, Buckle Adam, Ramsahoye Bernard, Bruton Peter C, Saleeb Rebecca S, Arnedo Maria, Hill Bill, Duncan Rory R, Maciver Sutherland K, Gilbert Nick
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK.
Edinburgh Super-Resolution Imaging Consortium, Institute of Biological Chemistry, Biophysics, and Bioengineering, Heriot-Watt University, Edinburgh EH14 4AS, UK.
Cell. 2017 Jun 15;169(7):1214-1227.e18. doi: 10.1016/j.cell.2017.05.029.
Higher eukaryotic chromosomes are organized into topologically constrained functional domains; however, the molecular mechanisms required to sustain these complex interphase chromatin structures are unknown. A stable matrix underpinning nuclear organization was hypothesized, but the idea was abandoned as more dynamic models of chromatin behavior became prevalent. Here, we report that scaffold attachment factor A (SAF-A), originally identified as a structural nuclear protein, interacts with chromatin-associated RNAs (caRNAs) via its RGG domain to regulate human interphase chromatin structures in a transcription-dependent manner. Mechanistically, this is dependent on SAF-A's AAA ATPase domain, which mediates cycles of protein oligomerization with caRNAs, in response to ATP binding and hydrolysis. SAF-A oligomerization decompacts large-scale chromatin structure while SAF-A loss or monomerization promotes aberrant chromosome folding and accumulation of genome damage. Our results show that SAF-A and caRNAs form a dynamic, transcriptionally responsive chromatin mesh that organizes large-scale chromosome structures and protects the genome from instability.
高等真核生物染色体被组织成拓扑受限的功能域；然而，维持这些复杂间期染色质结构所需的分子机制尚不清楚。曾有人提出一种支撑核组织的稳定基质，但随着染色质行为的更动态模型变得普遍，这一观点被摒弃。在此，我们报告称，支架附着因子A（SAF-A）最初被鉴定为一种结构性核蛋白，它通过其RGG结构域与染色质相关RNA（caRNAs）相互作用，以转录依赖的方式调节人类间期染色质结构。从机制上讲，这依赖于SAF-A的AAA ATP酶结构域，该结构域响应ATP结合和水解，介导与caRNAs的蛋白质寡聚化循环。SAF-A寡聚化使大规模染色质结构解压缩，而SAF-A缺失或单体化则促进异常染色体折叠和基因组损伤的积累。我们的结果表明，SAF-A和caRNAs形成了一个动态的、转录响应性的染色质网，该染色质网组织大规模染色体结构并保护基因组免受不稳定影响。
