Journal
NATURE CELL BIOLOGY
Volume 19, Issue 1, Pages 68-75Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncb3450
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Funding
- NIH [GM029513, HG007852]
- Ludwig Institute for Cancer Research
- Howard Hughes Medical Institute
- Cancer Cell Biology Training Grant from the NCI [5T32CA067754-18]
- Hope Funds for Cancer Research [HFCR-14-06-06]
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Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements(1,2) known as chromothripsis(3), 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.
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