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

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


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.

MeSH terms

  • Autoantigens / metabolism
  • Cell Line, Tumor
  • Centromere / metabolism*
  • Centromere Protein A
  • Centromere Protein B / metabolism
  • Chromosomal Proteins, Non-Histone / metabolism
  • Chromosome Segregation
  • Chromosomes, Human, Y / metabolism*
  • Chromothripsis*
  • DNA End-Joining Repair*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Micronuclei, Chromosome-Defective*
  • Mitosis


  • Autoantigens
  • CENPA protein, human
  • Centromere Protein A
  • Centromere Protein B
  • Chromosomal Proteins, Non-Histone