Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis
Chromosomal rearrangements can radically alter gene products and their function, driving tumor formation or progression. However, the molecular origins and evolution of such rearrangements are varied and poorly understood, with cancer cells often containing multiple, complex rearrangements. One mech...
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| Format: | Article |
| Language: | en_US |
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Springer-Verlag
2013
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| Online Access: | http://hdl.handle.net/1721.1/82625 https://orcid.org/0000-0002-3829-5612 |
| _version_ | 1826204411450359808 |
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| author | Gascoigne, Karen E. Cheeseman, Iain M |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Gascoigne, Karen E. Cheeseman, Iain M |
| author_sort | Gascoigne, Karen E. |
| collection | MIT |
| description | Chromosomal rearrangements can radically alter gene products and their function, driving tumor formation or progression. However, the molecular origins and evolution of such rearrangements are varied and poorly understood, with cancer cells often containing multiple, complex rearrangements. One mechanism that can lead to genomic rearrangements is the formation of a “dicentric” chromosome containing two functional centromeres. Indeed, such dicentric chromosomes have been observed in cancer cells. Here, we tested the ability of a single dicentric chromosome to contribute to genomic instability and neoplastic conversion in vertebrate cells. We developed a system to transiently and reversibly induce dicentric chromosome formation on a single chromosome with high temporal control. We find that induced dicentric chromosomes are frequently damaged and mis-segregated during mitosis, and that this leads to extensive chromosomal rearrangements including translocations with other chromosomes. Populations of pre-neoplastic cells in which a single dicentric chromosome is induced acquire extensive genomic instability and display hallmarks of cellular transformation including anchorage-independent growth in soft agar. Our results suggest that a single dicentric chromosome could contribute to tumor initiation. |
| first_indexed | 2024-09-23T12:54:39Z |
| format | Article |
| id | mit-1721.1/82625 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:54:39Z |
| publishDate | 2013 |
| publisher | Springer-Verlag |
| record_format | dspace |
| spelling | mit-1721.1/826252022-10-01T11:50:03Z Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis Gascoigne, Karen E. Cheeseman, Iain M Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Cheeseman, Iain McPherson Chromosomal rearrangements can radically alter gene products and their function, driving tumor formation or progression. However, the molecular origins and evolution of such rearrangements are varied and poorly understood, with cancer cells often containing multiple, complex rearrangements. One mechanism that can lead to genomic rearrangements is the formation of a “dicentric” chromosome containing two functional centromeres. Indeed, such dicentric chromosomes have been observed in cancer cells. Here, we tested the ability of a single dicentric chromosome to contribute to genomic instability and neoplastic conversion in vertebrate cells. We developed a system to transiently and reversibly induce dicentric chromosome formation on a single chromosome with high temporal control. We find that induced dicentric chromosomes are frequently damaged and mis-segregated during mitosis, and that this leads to extensive chromosomal rearrangements including translocations with other chromosomes. Populations of pre-neoplastic cells in which a single dicentric chromosome is induced acquire extensive genomic instability and display hallmarks of cellular transformation including anchorage-independent growth in soft agar. Our results suggest that a single dicentric chromosome could contribute to tumor initiation. Leukemia & Lymphoma Society of America (Scholar Award) National Institute of General Medical Sciences (U.S.) (Grant GM088313) American Cancer Society (Research Scholar Grant 121776) 2013-12-02T19:32:43Z 2013-12-02T19:32:43Z 2013-06 2013-05 Article http://purl.org/eprint/type/JournalArticle 0967-3849 1573-6849 http://hdl.handle.net/1721.1/82625 Gascoigne, Karen E., and Iain M. Cheeseman. “Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis.” Chromosome Research 21, no. 4 (July 22, 2013): 407-418. https://orcid.org/0000-0002-3829-5612 en_US http://dx.doi.org/10.1007/s10577-013-9368-6 Chromosome Research http://creativecommons.org/licenses/by/3.0/ application/pdf Springer-Verlag PMC |
| spellingShingle | Gascoigne, Karen E. Cheeseman, Iain M Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| title | Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| title_full | Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| title_fullStr | Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| title_full_unstemmed | Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| title_short | Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| title_sort | induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis |
| url | http://hdl.handle.net/1721.1/82625 https://orcid.org/0000-0002-3829-5612 |
| work_keys_str_mv | AT gascoignekarene induceddicentricchromosomeformationpromotesgenomicrearrangementsandtumorigenesis AT cheesemaniainm induceddicentricchromosomeformationpromotesgenomicrearrangementsandtumorigenesis |