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Nat Cell Biol. 2017 Jan;19(1):68-75. doi: 10.1038/ncb3450. Epub 2016 Dec 5.

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

Author information

1
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.
2
Department of Biology, Massachusetts Institute of Technology and Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
3
Howard Hughes Medical Institute and Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.

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.

PMID:
27918550
PMCID:
PMC5539760
DOI:
10.1038/ncb3450
[Indexed for MEDLINE]
Free PMC Article

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