DNA double strand break repair and chromosomal translocation: Lessons from animal models
Abstract
The maintenance of genomic stability is one of the most important defenses against neoplastic transformation. This objective must be accomplished despite a constant barrage of spontaneous DNA double strand breaks. These dangerous lesions are corrected by two primary pathways of double strand break repair; non homologous end joining and homologous recombination. Recent studies employing mouse models have shown that absence of either pathway leads to genomic instability, including potentially oncogenic translocations. Because translocations involve the union of different chromosomes, cellular machinery must exist that creates these structures in the context of unrepaired double strand breaks. Evidence is mounting that the pathways of double strand break repair that are so important for survival may themselves be the culprits that generate potentially fatal translocations. Evidence and models for the dual roles of double strand break repair in both preventing, and generating, oncogenic karyotypic changes are discussed.
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MEFs deficient for XRCC4, Ligase IV, Ku70, or Ku80 (but not DNA-PKcs or Artemis) senesce prematurely in culture.
“MEFs deficient for XRCC4, Ligase IV, Ku70, or Ku80 (but not DNA-PKcs or Artemis) senesce prematurely in culture”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ferguson and Alt, 2001
The premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants occur as a response to, rather than as a direct consequence of, unrepaired DSBs.
“Thus, the former phenotypes occur as a response to, rather than as a direct consequence of, unrepaired DSBs (Ferguson and Alt, 2001”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ferguson and Alt, 2001
Mice with targeted inactivating mutations in NHEJ genes display phenotypes that reflect loss of these functions.
“Mice with targeted inactivating mutations in NHEJ genes display phenotypes that reflect loss of these functions (Ferguson and Alt, 2001”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ferguson and Alt, 2001
p53-dependent responses are critical in mediating the premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants.
“p53-dependent responses are critical in mediating the premature senescence and neuronal apoptosis phenotypes of certain NHEJ mutants (Ferguson and Alt, 2001”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ferguson and Alt, 2001
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 [19]
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 [19]
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References 51 · Cited by 333
- Authors
- Ferguson, D. O., & Alt, F. W.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Alt, Frederick W
- Venue
- Oncogene
- Published
- 2001-09-10
- Volume
- 20
- Issue
- 40
- Pages
- 5572-5579
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2076328665
- Semantic Scholar
- 3b8f2a396a95409c84dc0426b19ee85d262e1d87
- Cited by
- 333
- References
- 51
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 10 · 2015: 10 · 2014: 10 · 2013: 13 · 2012: 14
- FWCI
- 1.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- 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
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Keywords
- DNA double-strand break repair, chromosomal translocation, genome stability, non-homologous end joining, homologous recombination, oncogenic translocation, karyotypic instability, mouse model, spontaneous DNA damage, oncogenic transformation
- MeSH terms
- Animals, Chromosomes, DNA Damage, DNA Repair, Models, Genetic, Recombination, Genetic, Translocation, Genetic, Mice
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