Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining
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 dir...
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| Format: | Article |
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Springer Nature
2018
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| Online Access: | http://hdl.handle.net/1721.1/116801 https://orcid.org/0000-0003-1783-2930 https://orcid.org/0000-0001-9920-3411 |
| _version_ | 1826195426359902208 |
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| author | Ly, Peter Kim, Dong H. Shoshani, Ofer Skaletsky, Helen Fachinetti, Daniele Cleveland, Don W. Teitz, Levi Shmuel Page, David C |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Ly, Peter Kim, Dong H. Shoshani, Ofer Skaletsky, Helen Fachinetti, Daniele Cleveland, Don W. Teitz, Levi Shmuel Page, David C |
| author_sort | Ly, Peter |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:12:27Z |
| format | Article |
| id | mit-1721.1/116801 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:12:27Z |
| publishDate | 2018 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | mit-1721.1/1168012022-09-26T16:28:24Z Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining Ly, Peter Kim, Dong H. Shoshani, Ofer Skaletsky, Helen Fachinetti, Daniele Cleveland, Don W. Teitz, Levi Shmuel Page, David C Massachusetts Institute of Technology. Department of Biology Teitz, Levi Shmuel Page, David C 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. National Institutes of Health (U.S.) (Grant HG007852) 2018-07-05T18:11:05Z 2018-07-05T18:11:05Z 2016-12 2016-04 2018-07-02T14:18:44Z Article http://purl.org/eprint/type/JournalArticle 1465-7392 1476-4679 http://hdl.handle.net/1721.1/116801 Ly, Peter et al. “Selective Y Centromere Inactivation Triggers Chromosome Shattering in Micronuclei and Repair by Non-Homologous End Joining.” Nature Cell Biology 19, 1 (December 2016): 68–75 https://orcid.org/0000-0003-1783-2930 https://orcid.org/0000-0001-9920-3411 http://dx.doi.org/10.1038/NCB3450 Nature Cell Biology Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Springer Nature PMC |
| spellingShingle | Ly, Peter Kim, Dong H. Shoshani, Ofer Skaletsky, Helen Fachinetti, Daniele Cleveland, Don W. Teitz, Levi Shmuel Page, David C Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| title | Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| title_full | Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| title_fullStr | Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| title_full_unstemmed | Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| title_short | Selective Y centromere inactivation triggers chromosome shattering in micronuclei and repair by non-homologous end joining |
| title_sort | selective y centromere inactivation triggers chromosome shattering in micronuclei and repair by non homologous end joining |
| url | http://hdl.handle.net/1721.1/116801 https://orcid.org/0000-0003-1783-2930 https://orcid.org/0000-0001-9920-3411 |
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