Chromosomes function as a barrier to mitotic spindle bipolarity in polyploid cells

Abstract

Whole genome duplications (WGDs) are found in a variety of tumors and are associated with chromosomal instability (CIN) and poor prognosis [1,2]. When induced experimentally, through cytokinesis failure, polyploid cells generate tumors [3]. Cytokinesis failure results in the accumulation of double DNA content, but also of cytoplasmic organelles, such as centrosomes, which are the major microtubule (MT) organizing centers of animal cells. Importantly, even if there is a correlation between polyploidy and CIN [4], the underlying mechanisms generating error-prone mitosis in cells with extra DNA and extra centrosomes are not known. When considering polyploid mitosis, it is essential to take into account the increase in MT nucleation due to the presence of extra centrosomes and extra DNA. The presence of supernumerary centrosomes in a cell, centrosome amplification [5], is associated with mitotic spindle multipolarity and CIN [6-9]. Importantly, additional MTs can be nucleated from the chromatin (chromatin mediated pathway-CMP) or from pre-existing MTs-through the Augmin pathway. We hypothesized that the increase in DNA and centrosome content in a cell could lead to an increased MT mass, which might account for abnormal mitosis described in polyploid cells [4, 10, 11, 12]. Using genetics, live imaging and modeling approaches, we investigated the mechanisms establishing multipolarity in vivo in polyploid cells. We found that MT nucleation from the centrosomes is the major contributor to multipolarity, while other pathways seem to play minor roles. Unexpectedly, we found that even if Ncd/HSET, plays an essential role in promoting centrosome clustering in early mitosis, the increase in chromosome mass associated with cytokinesis failure functions as a barrier to centrosome clustering into two main poles. Our work provides a mechanistic link between polyploidy and the generation of CIN.