Frequent chromosomal translocations induced by DNA double-strand breaks
Abstract
The faithful repair of DNA damage such as chromosomal double-strand breaks (DSBs) is crucial for genomic integrity. Aberrant repair of these lesions can result in chromosomal rearrangements, including translocations, which are associated with numerous tumours. Models predict that some translocations arise from DSB-induced recombination in differentiating lymphoid cell types or from aberrant repair of DNA damage induced by irradiation or other agents; however, a genetic system to study the aetiology of these events has been lacking. Here we use a mouse embryonic stem cell system to examine the role of DNA damage on the formation of translocations. We find that two DSBs, each on different chromosomes, are sufficient to promote frequent reciprocal translocations. The results are in striking contrast with interchromosomal repair of a single DSB in an analogous system in which translocations are not recovered. Thus, while interchromosomal DNA repair does not result in genome instability per se, the presence of two DSBs in a single cell can alter the spectrum of repair products that are recovered.
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NHEJ is error-prone and can cause genome structural variations, potentially leading to gene fusions with pathological gain or loss of function.
“NEHJ is error-prone and can cause genome structural variations, potentially leading to gene fusions with pathological gain or loss of function”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [18]
DSBs are repaired via the classical non-homologous end joining (NHEJ) pathway in post-mitotic cells and can lead to genome structural variations.
“DSBs are repaired via the classical non-homologous end joining (NHEJ) pathway in post-mitotic cells and can lead to genome structural variations”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [18]
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- Authors
- Richardson, C., & Jasin, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Jasin, Maria
- Venue
- Nature
- Published
- 2000-06
- Volume
- 405
- Issue
- 6787
- Pages
- 697-700
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1509538618
- Cited by
- 517
- References
- 32
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 7 · 2023: 8 · 2022: 11 · 2021: 15 · 2020: 19 · 2019: 13 · 2018: 17 · 2017: 16 · 2016: 25 · 2015: 18 · 2014: 18 · 2013: 18 · 2012: 19
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Science Foundation
- Leukemia and Lymphoma Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- chromosomal translocation, DNA double-strand breaks, DNA repair, reciprocal translocation, genomic instability, mouse embryonic stem cells, lymphoid differentiation, tumour aetiology, recombination
- MeSH terms
- Animals, Cell Line, DNA, DNA Damage, DNA Repair, Gene Conversion, Recombination, Genetic, Stem Cells, Translocation, Genetic, Blotting, Southern, Polymerase Chain Reaction, Kanamycin Kinase, Mice
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