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

• Published in: Nature cell biology Vol. 19; no. 1; pp. 68 - 75
• Main Authors: Ly, Peter, Teitz, Levi S., Kim, Dong H., Shoshani, Ofer, Skaletsky, Helen, Fachinetti, Daniele, Page, David C., Cleveland, Don W.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2017; Nature Publishing Group
• Subjects: 631/80/103/90; 631/80/641/1655; 631/80/641/2002; Autoantigens - metabolism; Biological research; Biology, Experimental; Biomedical research; Cancer Research; Cell Biology; Cell cycle; Cell division; Cell Line, Tumor; Centromere - metabolism; Centromere Protein A; Centromere Protein B - metabolism; Centromeres; Chromosomal Proteins, Non-Histone - metabolism; Chromosome Segregation; Chromosomes; Chromosomes, Human, Y - metabolism; Chromothripsis; Developmental Biology; DNA damage; DNA End-Joining Repair; DNA repair; Humans; In Situ Hybridization, Fluorescence; Inactivation; letter; Life Sciences; Medical research; Micronuclei, Chromosome-Defective; Mitosis; Molecular biology; Physiological aspects; Proteins; Stem Cells; Y chromosome; Y chromosomes; United States; United States > US; Massachusetts; California
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3450

Ly et al.  establish a method to selectively inactivate the centromere of the Y chromosome to follow chromosome shattering and micronuclei formation through several cell cycles, and suggest re-ligation of chromosome fragments is dependent on non-homologous end joining. 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.