PDF(Pubmed)
Abstract：
DNA replication and transcription generate DNA supercoiling, which can cause topological stress and intertwining of daughter chromatin fibers, posing challenges to the completion of DNA replication and chromosome segregation. Type II topoisomerases (Top2s) are enzymes that relieve DNA supercoiling and decatenate braided sister chromatids. How Top2 complexes deal with the topological challenges in different chromatin contexts, and whether all chromosomal contexts are subjected equally to torsional stress and require Top2 activity is unknown. Here we show that catalytic inhibition of the Top2 complex in interphase has a profound effect on the stability of heterochromatin and repetitive DNA elements. Mechanistically, we find that catalytically inactive Top2 is trapped around heterochromatin leading to DNA breaks and unresolved catenates, which necessitate the recruitment of the structure specific endonuclease, Ercc1-XPF, in an SLX4- and SUMO-dependent manner. Our data are consistent with a model in which Top2 complex resolves not only catenates between sister chromatids but also inter-chromosomal catenates between clustered repetitive elements.
摘要：
DNA复制和转录产生DNA超螺旋，会引起拓扑应力和子染色质纤维的交织，对完成DNA复制和染色体分离构成挑战。II型拓扑异构酶（Top2s）是减轻DNA超螺旋和癸酸编织姐妹染色单体的酶。Top2复合物如何应对不同染色质背景下的拓扑挑战，以及是否所有染色体环境都同样受到扭转应力并需要Top2活性是未知的。在这里，我们表明，介相中Top2复合物的催化抑制对异染色质和重复DNA元件的稳定性具有深远的影响。机械上,我们发现无催化活性的Top2被困在异染色质周围，导致DNA断裂和未解决的连接，这需要募集结构特异性核酸内切酶，Ercc1-XPF,以SLX4和SUMO依赖的方式。我们的数据与模型一致，在该模型中，Top2复合物不仅可以解决姐妹染色单体之间的连接，还可以解决聚类重复元件之间的染色体间连接。
