Induced dicentric chromosome formation promotes genomic rearrangements and tumorigenesis
Open accessAbstract
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.
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Even limited telomere dysfunction can cause widespread genome instability because instability at individual chromosome ends can transfer to other chromosomes through non-reciprocal translocations.
“Even limited telomere dysfunction can wreak havoc on the genome because instability at individual chromosome ends can be transferred to other chromosomes through non-reciprocal translocations172,173.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [173]
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Telomeres in cancer: tumour suppression and genome instability
Maciejowski, J., & de Lange, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2016.171 · Cited by 745 · see citing works
- Authors
- Gascoigne, K. E., & Cheeseman, I. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Corresponding author
- Cheeseman, Iain M.
- Venue
- Chromosome Research
- Published
- 2013-06-22
- Volume
- 21
- Issue
- 4
- Pages
- 407-418
- ISSN
- 0967-3849 (ISSN-L)
- 1573-6849
- PMC
- PMC3713265
- OpenAlex
- W2011713726
- Cited by
- 65
- References
- 34
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 7 · 2022: 7 · 2021: 5 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 8 · 2014: 4 · 2013: 1
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Chromosome Research (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- American Cancer Society (121776)
- National Institutes of Health
- National Institute of General Medical Sciences (GM088313, R01GM088313)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- dicentric chromosomes, genome rearrangement, chromosomal instability, carcinogenesis, translocation, centromere, cell transformation, anchorage-independent growth, tumor initiation
- MeSH terms
- Animals, Centromere, Chromosome Aberrations, Fluorescent Antibody Technique, Mitosis, Translocation, Genetic, Gene Rearrangement, In Situ Hybridization, Fluorescence, Genomics, Genomic Instability, Cell Line, Tumor, Mice, Carcinogenesis
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