Selective y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining

Peter Ly, Levi S. Teitz, Dong H. Kim, Ofer Shoshani, Helen Skaletsky, Daniele Fachinetti, David C. Page, Don W. Cleveland

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements known as chromothripsis, but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles. Following centromere inactivation, a micronucleus harbouring the Y chromosome is formed in the first cell cycle. Chromosome shattering, producing up to 53 dispersed fragments from a single chromosome, is triggered by premature micronuclear condensation prior to or during mitotic entry of the second cycle. Lastly, canonical non-homologous end joining (NHEJ), but not homology-dependent repair, is shown to facilitate re-ligation of chromosomal fragments in the third cycle. Thus, initial errors in cell division can provoke further genomic instability through fragmentation of micronuclear DNAs coupled to NHEJ-mediated reassembly in the subsequent interphase.

Original languageEnglish (US)
Pages (from-to)68-75
Number of pages8
JournalNature cell biology
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Cell Biology

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    Ly, P., Teitz, L. S., Kim, D. H., Shoshani, O., Skaletsky, H., Fachinetti, D., Page, D. C., & Cleveland, D. W. (2017). Selective y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. Nature cell biology, 19(1), 68-75. https://doi.org/10.1038/ncb3450