| PubMed ID |
|
27918550 |
Publish Date |
|
2017 Jan |
| Journal |
|
Nat Cell Biol |
Species |
|
|
| Disease Type |
|
|
Technology |
|
|
| Title |
|
Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| Authors |
|
Ly P, Teitz LS, Kim DH, Shoshani O, Skaletsky H, Fachinetti D, Page DC, Cleveland DW |
| Affiliation |
|
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA |
| Chromothripsis Definition |
|
Close-by breakpoints: NA
Copy number states: NA
Fragments random joining: NA |
| 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. |
|
