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

Nature Cell Biology 19, 68 (2017). doi:10.1038/ncb3450 Authors: Peter Ly, Levi S. Teitz, Dong H. Kim, Ofer Shoshani, Helen Skaletsky, Daniele Fachinetti, David C. Page & Don W. Cleveland 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.
Source: Nature Cell Biology - Category: Cytology Authors: Tags: Letter Source Type: research