Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining.
Nat Cell Biol
; 19(1): 68-75, 2017 Jan.
Article
em En
| MEDLINE
| ID: mdl-27918550
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Centrômero
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Cromossomos Humanos Y
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Micronúcleos com Defeito Cromossômico
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Reparo do DNA por Junção de Extremidades
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Cromotripsia
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article