Chromosome Bridges Maintain Kinetochore-Microtubule Attachment throughout Mitosis and Rarely Break during Anaphase

PLoS One. 2016 Jan 19;11(1):e0147420. doi: 10.1371/journal.pone.0147420. eCollection 2016.

Abstract

Accurate chromosome segregation during cell division is essential to maintain genome stability, and chromosome segregation errors are causally linked to genetic disorders and cancer. An anaphase chromosome bridge is a particular chromosome segregation error observed in cells that enter mitosis with fused chromosomes/sister chromatids. The widely accepted Breakage/Fusion/Bridge cycle model proposes that anaphase chromosome bridges break during mitosis to generate chromosome ends that will fuse during the following cell cycle, thus forming new bridges that will break, and so on. However, various studies have also shown a link between chromosome bridges and aneuploidy and/or polyploidy. In this study, we investigated the behavior and properties of chromosome bridges during mitosis, with the idea to gain insight into the potential mechanism underlying chromosome bridge-induced aneuploidy. We find that only a small number of chromosome bridges break during anaphase, whereas the rest persist through mitosis into the subsequent cell cycle. We also find that the microtubule bundles (k-fibers) bound to bridge kinetochores are not prone to breakage/detachment, thus supporting the conclusion that k-fiber detachment is not the cause of chromosome bridge-induced aneuploidy. Instead, our data suggest that while the microtubules bound to the kinetochores of normally segregating chromosomes shorten substantially during anaphase, the k-fibers bound to bridge kinetochores shorten only slightly, and may even lengthen, during anaphase. This causes some of the bridge kinetochores/chromosomes to lag behind in a position that is proximal to the cell/spindle equator and may cause the bridged chromosomes to be segregated into the same daughter nucleus or to form a micronucleus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anaphase / physiology*
  • Cells, Cultured
  • Chromosome Segregation / physiology*
  • Chromosomes, Human / genetics
  • HeLa Cells
  • Humans
  • Kinetochores / physiology*
  • Mammary Glands, Human / cytology*
  • Mammary Glands, Human / metabolism
  • Microtubules / physiology*
  • Mitosis / physiology*

Grants and funding

This work was partly funded by the Commonwealth Research Initiative and the Fralin Research Institute. Additional funding was provided by: NSF grants MCB-0842551 and MCB-1517506 and HFSP grant RGY0069/2010 to DC; EURATOM grant Dark. Risk GA 323216 and CSN2012-0001 grant to AG; Ministerio de Economía y Competitividad grant SAF2013-43801-P to LT; Instituto de Salud Carlos III grant RD06/0020/1020 and Generalitat de Catalunya grants 2009 SGR-282 and 2014 SGR-524 to AG and LT. JP was supported by Generalitat de Catalunya (grants 2007FIC-00642 and 2008BE1 00443). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.