Chromosomes missegregated into micronuclei contribute to chromosomal instability by missegregating at the next division.

Bin He,Alyssa Osimani,Aaron J Mattingly,Nisha Gnawali,Daniela Cimini,Albert W Hinman

doi:10.18632/oncotarget.26853

Abstract

Micronuclei (MNi) are extranuclear DNA-containing structures that form upon mitotic exit from unsegregated chromosome fragments or anaphase lagging (whole) chromosomes (LCs). MNi formed from whole chromosomes are of particular interest because LCs are observed in both cancer and non-cancer cells, and are recognized as a major source of chromosomal instability (CIN) in cancer cells. Here, we generated a PtK1 cell line expressing a photoactivatable H2B histone to study the behavior of whole chromosome-containing MNi at the mitosis following their formation. Importantly, MNi of PtK1 cells did not display the membrane rupture or transport defects reported for other cell types. Despite this, we found that most micronucleated cells displayed some kind of chromosome segregation defect and that the missegregating chromosome was the one derived from the MN. Moreover, condensation of the chromosome within the MN was frequently delayed and associated with failure to align at the metaphase plate. Finally, the defective condensation of the MN-derived chromosomes could also explain the frequent occurrence of cytokinesis failure in micronucleated cells. In summary, we find that chromosomes from MNi may trigger a CIN phenotype by missegregating at the mitosis following MN formation.

Highlights

Segregation of sister chromatids to opposite spindle poles during mitosis ensures equal chromosome distribution between the daughter cells
We investigated the fate of newly formed whole chromosome-containing MNi in PtK1 cells, an experimental model that does not appear to suffer from rupture of the MN membrane or major defects in transport across the membrane
These phenotypes have been reported for several different human cell types [12, 13, 15,16,17] and can explain the abnormal mitotic behavior of chromosomes trapped in MNi in some of these cell types [12, 19, 20]

Summary

Introduction

Segregation of sister chromatids to opposite spindle poles during mitosis ensures equal chromosome distribution between the daughter cells. This is achieved through the attachment of sister chromatids to microtubules from opposite spindle poles in early mitosis. This attachment occurs at a specialized proteinaceous structure known as the kinetochore (KT), which assembles at the centromeric region of the chromosome. Individual sister chromatids can establish incorrect merotelic KT attachment by binding microtubules from both spindle poles [1]. Chromosome fragments present at mitosis are unable to move to the spindle pole and form micronuclei (MNi) upon mitotic exit. The frequency of MNi increases with age and is a biomarker for increased cancer risk [8, 9]

Methods

Results

Conclusion