Abstract:
Chromatin bridges are strings of mis-segregated chromatin connecting the anaphase poles or daughter nuclei in mitotic cell division and can arise from incomplete DNA replication or decatenation, or from dicentric chromosomes generated by end-to-end chromosome fusions. Chromatin bridges pose a major threat for genome integrity because, if unsupported, they can lead to chromatin bridge breakage-fusion-bridge cycles or to chromothripsis, which can cause burst-like accumulation of genomic alterations that can drive carcinogenesis. As a result, preventing chromatin bridges from breaking is essential for cells to maintain genome stability. For this purpose, human cells use at least two major mechanisms to stabilize chromatin bridges: Firstly, they impose an abscission-delay, called “the abscission checkpoint”, to prevent chromatin breakage or tetraploidization by regression of the cleavage furrow. Secondly, they generate accumulations of polymerized actin, called “actin patches” at the base of the intercellular canal to stabilize chromatin bridges and prevent them from breaking. Recent findings from our lab shed light into how chromatin bridges are sensed by the cell and into the molecular mechanisms involved. We show that Topoisomerase IIα, an enzyme that can untangle catenated DNA molecules, recognizes “knotted” DNA on chromatin bridges and triggers a downstream MRN-ATM-Chk2-INCENP signaling pathway to delay abscission and prevent chromatin breakage. We also show that daughter nuclei connected by chromatin bridges are under mechanical tension that requires interaction of a mechanosensing nuclear envelope protein complex with the actin cytoskeleton. This nuclear tension promotes local enrichment of a small Rho GTPase that modulates the actin cytoskeleton at the base of the intercellular canal, to generate actin patches and prevent chromatin bridge breakage in cytokinesis. These findings describe basic mechanisms that maintain genome stability in human cells and can protect against tumorigenesis.
