Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining
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Author(s)
Ly, Peter
Kim, Dong H.
Shoshani, Ofer
Skaletsky, Helen
Fachinetti, Daniele
Cleveland, Don W.
Teitz, Levi Shmuel
Page, David C
Date Issued
December 2016
Journal
Nature Cell Biology
Publisher
Springer Nature
Citation
Ly, Peter et al. “Selective Y Centromere Inactivation Triggers Chromosome Shattering in Micronuclei and Repair by Non-Homologous End Joining.” Nature Cell Biology 19, 1 (December 2016): 68–75
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Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/NCB3450
