期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：10
DOI：10.1073/pnas.2123363119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
A central feature of mitosis is segregation of sister chromatids to opposite poles during anaphase. Our recent work revealed that sister chromatids are linked by robust structural bridges built on topological sister/sister catenations. This unexpected finding implies that separation of sister chromatids is more complex than previously thought. The present study reveals that bridges are removed in a highly programmed three-stage process, all licensed by anaphase onset and cohesin removal, and all promoted by distinct types of intersister separation forces. Removal of bridge-associated cohesin and topoisomerase II–mediated decatenation plays a central role. These findings raise the possibility that the presence and programmed removal of bridges are required for smooth, synchronous, and regular movement of sisters to opposite poles.
During mitosis, from late prophase onward, sister chromatids are connected along their entire lengths by axis-linking chromatin/structure bridges. During prometaphase/metaphase, these bridges ensure that sister chromatids retain a parallel, paranemic relationship, without helical coiling, as they undergo compaction. Bridges must then be removed during anaphase. Motivated by these findings, the present study has further investigated the process of anaphase sister separation. Morphological and functional analyses of mammalian mitoses reveal a three-stage pathway in which interaxis bridges play a prominent role. First, sister chromatid axes globally separate in parallel along their lengths, with concomitant bridge elongation, due to intersister chromatin pushing forces. Sister chromatids then peel apart progressively from a centromere to telomere region(s), step-by-step. During this stage, poleward spindle forces dramatically elongate centromere-proximal bridges, which are then removed by a topoisomerase IIα–dependent step. Finally, in telomere regions, widely separated chromatids remain invisibly linked, presumably by catenation, with final separation during anaphase B. During this stage increased separation of poles and/or chromatin compaction appear to be the driving force(s). Cohesin cleavage licenses these events, likely by allowing bridges to respond to imposed forces. We propose that bridges are not simply removed during anaphase but, in addition, play an active role in ensuring smooth and synchronous microtubule-mediated sister separation. Bridges would thereby be the topological gatekeepers of sister chromatid relationships throughout all stages of mitosis.
