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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.

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


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.

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