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

66 Citations (Scopus)

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
Externally publishedYes

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Centromere
Chromosomes
Ligation
Cell Cycle
Genomic Instability
Y Chromosome
Interphase
DNA Fragmentation
Diploidy
Cell Division
Histones
Chromothripsis

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ly, P., Teitz, L. S., Kim, D. H., Shoshani, O., Skaletsky, H., Fachinetti, D., ... 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

Selective y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. / Ly, Peter; Teitz, Levi S.; Kim, Dong H.; Shoshani, Ofer; Skaletsky, Helen; Fachinetti, Daniele; Page, David C.; Cleveland, Don W.

In: Nature Cell Biology, Vol. 19, No. 1, 01.01.2017, p. 68-75.

Research output: Contribution to journalArticle

Ly, P, Teitz, LS, Kim, DH, Shoshani, O, Skaletsky, H, Fachinetti, D, Page, DC & Cleveland, DW 2017, 'Selective y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining', Nature Cell Biology, vol. 19, no. 1, pp. 68-75. https://doi.org/10.1038/ncb3450
Ly, Peter ; Teitz, Levi S. ; Kim, Dong H. ; Shoshani, Ofer ; Skaletsky, Helen ; Fachinetti, Daniele ; Page, David C. ; Cleveland, Don W. / Selective y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining. In: Nature Cell Biology. 2017 ; Vol. 19, No. 1. pp. 68-75.
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