Details

Autor(en) / Beteiligte

• Ly, Peter
• Teitz, Levi S
• Kim, Dong H
• Shoshani, Ofer
• Skaletsky, Helen
• Fachinetti, Daniele
• Page, David C
• Cleveland, Don W

Titel

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

Ist Teil von

• Nature cell biology, 2017-01, Vol.19 (1), p.68

Ort / Verlag

England

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.