Biswajit Pradhan, Adrian Pinto, Takaharu Kanno, Damla Tetiker, Martin D. Baaske, Erin Cutt, Constantinos Chatzicharlampous, Herwig Schüler, Amar Deep, Kevin D. Corbett, Luis Aragon, Peter Virnau, Camilla Björkegren, Eugene Kim
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引用次数: 0
Abstract
Structural maintenance of chromosome (SMC) complexes organize and regulate genomes via DNA loop extrusion. During this process, the complexes increase the loop size by reeling in DNA from one or both sides of the loop. The factors governing this symmetry remain unclear. Here, we combine single-molecule analysis and molecular dynamic simulations to investigate the symmetry of loop extrusion of various SMC complexes. We find that whereas monomeric condensin and cohesin are one-sided extruders, the symmetry of dimeric SMCs, such as Smc5/6 and Wadjet, is DNA tension dependent. At low DNA tension (< 0.1pN), Smc5/6 and Wadjet extrude DNA from both sides of the loop. At higher tension, however, they transition to a behavior akin to one-sided extruders, yet still capable of extruding from one or the other side thereby switching the direction of extrusion. Our simulations further reveal that thermal fluctuations significantly influence loop extrusion symmetry, causing variations in DNA reeling rates between the two motors in the dimeric complexes and their direction switching at stalling tensions. Our findings challenge the previous view of loop extrusion symmetry as a fixed characteristic, revealing its dynamic nature and regulation by both intrinsic protein properties and extrinsic factors.
染色体结构维护(SMC)复合物通过 DNA 环挤压来组织和调节基因组。在这一过程中,复合体通过从环路的一侧或两侧卷入 DNA 来增加环路的大小。调节这种对称性的因素仍不清楚。在这里,我们结合单分子分析和分子动力学模拟来研究各种 SMC 复合物环挤压的对称性。我们发现,单体凝集素和凝聚素是单侧挤出的,而二聚体 SMC(如 Smc5/6 和 Wadjet)的对称性则取决于 DNA 张力。在 DNA 张力较低(0.1pN)时,Smc5/6 和 Wadjet 从环路两侧挤出 DNA。然而,在张力较高时,它们会过渡到类似于单侧挤出器的行为,但仍能从一侧或另一侧挤出,从而转换挤出方向。我们的模拟进一步揭示了热波动对环路挤压对称性的显著影响,导致二聚体复合物中两个马达之间的DNA卷绕率发生变化,以及它们在张力失速时的方向切换。我们的发现挑战了以往将环路挤压对称性视为固定特性的观点,揭示了其动态性质以及受蛋白质内在特性和外在因素的调控。