ArticlePLoS genetics2014
Knock-in reporter mice demonstrate that DNA repair by non-homologous end joining declines with age.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 1 of them a synthesis that pooled it.
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Who cites it
72 citing papers in PubMed, 1 synthesis or guideline pooled it, 117 citations in OpenAlex.
- DNA damage-associated oligodendrocyte degeneration precedes amyloid pathology and contributes to Alzheimer's disease and dementia.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2018Pooled it
- Cancer-associated fusion transcripts: mechanisms, functional roles, and clinical implications.Clinical and experimental medicine · 2026Review
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- Aging alters DNA structure-induced genetic instability in mice.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Shared molecular mechanisms in aging and neurodegenerative diseases: from mechanistic insights to therapeutic strategies.Frontiers in human neuroscience · 2026Review
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- FOXO3a upregulates DNA repair activities by transcriptional activation of target genes and provides the resistance to gamma radiation and the extension of lifespan in mouse.Biogerontology · 2025Article
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- Age-dependent cytokine surge in blood precedes cancer diagnosis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- FNDC5/irisin mitigates the cardiotoxic impacts of cancer chemotherapeutics by modulating ROS-dependent and -independent mechanisms.Redox biology · 2025Article
- Novel Techniques for Mapping DNA Damage and Repair in the Brain.International journal of molecular sciences · 2024Review
- Modelling the In Vivo and Ex Vivo DNA Damage Response after Internal Irradiation of Blood from Patients with Thyroid Cancer.International journal of molecular sciences · 2024Article
- The NDR family of kinases: essential regulators of aging.Frontiers in molecular neuroscience · 2024Review
- Somatic mutation as an explanation for epigenetic aging.bioRxiv : the preprint server for biology · 2023Article
- Impaired end joining induces cardiac atrophy in a Hutchinson-Gilford progeria mouse model.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Genomic Instability and Epigenetic Changes during Aging.International journal of molecular sciences · 2023Review
- Article
- Ageing in the brain: mechanisms and rejuvenating strategies.Cellular and molecular life sciences : CMLS · 2023Review
- IDDoR: a novel reporter mouse system for simultaneous and quantitative in vivo analysis of both DNA double-strand break repair pathways.Protein & cell · 2023Article
- Biomarkers of aging.Science China. Life sciences · 2023Review
12 more citing papers are in PubMed but not listed here.
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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Accumulation of genome rearrangements is a characteristic of aged tissues. Since genome rearrangements result from faulty repair of DNA double strand breaks (DSBs), we hypothesized that DNA DSB repair becomes less efficient with age. The Non-Homologous End Joining (NHEJ) pathway repairs a majority of DSBs in vertebrates. To examine age-associated changes in NHEJ, we have generated an R26NHEJ mouse model in which a GFP-based NHEJ reporter cassette is knocked-in to the ROSA26 locus. In this model, NHEJ repair of DSBs generated by the site-specific endonuclease, I-SceI, reconstitutes a functional GFP gene. In this system NHEJ efficiency can be compared across tissues of the same mouse and in mice of different age. Using R26NHEJ mice, we found that NHEJ efficiency was higher in the skin, lung, and kidney fibroblasts, and lower in the heart fibroblasts and brain astrocytes. Furthermore, we observed that NHEJ efficiency declined with age. In the 24-month old animals compared to the 5-month old animals, NHEJ efficiency declined 1.8 to 3.8-fold, depending on the tissue, with the strongest decline observed in the skin fibroblasts. The sequence analysis of 300 independent NHEJ repair events showed that, regardless of age, mice utilize microhomology sequences at a significantly higher frequency than expected by chance. Furthermore, the frequency of microhomology-mediated end joining (MMEJ) events increased in the heart and lung fibroblasts of old mice, suggesting that NHEJ becomes more mutagenic with age. In summary, our study provides a versatile mouse model for the analysis of NHEJ in a wide range of tissues and demonstrates that DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.