A natural variation-based screen in mouse cells reveals USF2 as a regulator of the DNA damage response and cellular senescence
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Abstract
Cellular senescence is a program of cell cycle arrest, apoptosis resistance, and cytokine release induced by stress exposure in metazoan cells. Landmark studies in laboratory mice have characterized a number of master senescence regulators, including p16INK4a, p21, NF-κB, p53, and C/EBPβ. To discover other molecular players in senescence, we developed a screening approach to harness the evolutionary divergence between mouse species. We found that primary cells from the Mediterranean mouse Mus spretus, when treated with DNA damage to induce senescence, produced less cytokine and had less-active lysosomes than cells from laboratory Mus musculus. We used allele-specific expression profiling to catalog senescence-dependent cis-regulatory variation between the species at thousands of genes. We then tested for correlation between these expression changes and interspecies sequence variants in the binding sites of transcription factors. Among the emergent candidate senescence regulators, we chose a little-studied cell cycle factor, upstream stimulatory factor 2 (USF2), for molecular validation. In acute irradiation experiments, cells lacking USF2 had compromised DNA damage repair and response. Longer-term senescent cultures without USF2 mounted an exaggerated senescence regulatory program—shutting down cell cycle and DNA repair pathways, and turning up cytokine expression, more avidly than wild-type. We interpret these findings under a model of pro-repair, anti-senescence regulatory function by USF2. Our study affords new insights into the mechanisms by which cells commit to senescence, and serves as a validated proof of concept for natural variation-based regulator screens.
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These two factors have been primarily reported to induce senescence in prostate cancer and repress senescence in mice primary tail fibroblast cells, consistent with our findings.
“While there is no previous evidence supporting the broad senescence features of these two factors, they have been primarily reported to induce senescence in prostate cancer and repress senescence in mice primary tail fibroblast cells, respectively,113,114 which is consistent with our findings.”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [114]
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Bouafia, A., Corre, S., Gilot, D., Mouchet, N., Prince, S., & Galibert, M. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004309 · Cited by 41 · see citing works
Tumor-suppression function of transcription factor USF2 in prostate carcinogenesis
Chen, N., Szentirmay, M. N., Pawar, S. A., Sirito, M., Wang, J., Wang, Z., Zhai, Q., Yang, H.-X., Peehl, D. M., Ware, J. L., et al. (2005) · Oncogene · doi:10.1038/sj.onc.1209079 · Cited by 41 · see citing works
Loss of USF2 promotes proliferation, migration and mitophagy in a redox-dependent manner
Chi, T. F., Khoder‐Agha, F., Mennerich, D., Kellokumpu, S., Miinalainen, I., Kietzmann, T., & Dimova, E. Y. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101750 · Cited by 37 · see citing works
Early growth response 2 (EGR2) is a novel regulator of the senescence programme
Tyler, E. J., del Arroyo, A. G., Wallis, R., Hughes, B., Garbe, J. C., Stampfer, M. R., Koh, J., Lowe, R., Philpott, M. P., & Bishop, C. L. (2021) · Aging Cell · doi:10.1111/acel.13318 · Cited by 34 · see citing works
Pawar, S. A., Szentirmay, M. N., Hermeking, H., & Sawadogo, M. (2004) · Oncogene · doi:10.1038/sj.onc.1207806 · Cited by 32 · see citing works
Transcriptional responses to DNA damage
Silva, E., & Ideker, T. (2019) · DNA repair · doi:10.1016/j.dnarep.2019.05.002 · Cited by 31 · cited 1× · see citing works
“Most salient was a trend of pervasive repression 444 transcriptome-wide six hours after irradiation, which was detected in control cells as expected 445 (66,67), and was blunted in cells with Usf2 knocked down.”
BackgroundPAI‐1 transcriptional regulation during the G0 → G1 transition in human epidermal keratinocytes
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USF-1 Is Critical for Maintaining Genome Integrity in Response to UV-Induced DNA Photolesions
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Characterization of sequence determinants of enhancer function using natural genetic variation
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Mus spretus SEG/Pas mice resist virulent Yersinia pestis, under multigenic control
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ID1 inhibits USF2 and blocks TGF-β-induced apoptosis in mesangial cells
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Uncovering Divergence in Gene Expression Regulation in the Adaptation of Yeast to Nitrogen Scarcity
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Schistosoma mansoniexperimental infection inMus spretus(SPRET/EiJ strain) mice
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Target Inhibition of CBP Induced Cell Senescence in BCR-ABL- T315I Mutant Chronic Myeloid Leukemia
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Flagged first, then by citations
1 of the 113 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
Tao, W., Yu, Z., & Han, J.-D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.009 · Cited by 147 · see citing works
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Influence of Scaffold Topography and Culture Duration on Fibroblast Morphology in Tissue Engineering
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Combined Endurance and Resistance Exercise Mitigates Age‐Associated Cardiac Dysfunction
Han, X., Ashraf, M. Z., Shi, H., Nkembo, A. T., Tipparaju, S. M., & Xuan, W. (2024) · Advanced Biology · doi:10.1002/adbi.202400137 · Cited by 3 · see citing works
Elevated lysosomal mass and enzyme activity in fibroblasts of the Mediterranean mouse Mus spretus
Sui, M., Teh, J., Fort, K. A., Shaw, D. E., Sudmant, P. H., Koide, T., Good, J. M., Vázquez, J. M., & Brem, R. B. (2026) · Biology Letters · doi:10.1098/rsbl.2025.0479 · Cited by 1 · see citing works
Self-citationFeng, T., Zhang, Z., Wang, H., Zang, X., Zhang, J., Jiang, Y., Cui, Y., Duan, Y., Guo, R., Gao, Y., et al. (2026) · The Journal of Immunology · doi:10.1093/jimmun/vkag029 · Cited by 1 · see citing works
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Patel, T., Schwarz, R. J., Riege, K., Varshavsky, M., Kestler, H. A., Kaplan, T., Hoffmann, S., & van Bömmel, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.07.680024
Enhancing the performance and interpretability of epigenetic clocks
Patel, T., Schwarz, R. J., Riege, K., Varshavsky, M., Richmond, A., Marioni, R. E., Kestler, H. A., Kaplan, T., Hoffmann, S., & van Bömmel, A. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag661
Dimova, E. Y., & Kietzmann, T. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104348
- Authors
- Kang, T., Moore, E. C., Kopania, E. E. K., King, C. D., Schilling, B., Campisi, J., Good, J. M., & Brem, R. B.
- Affiliations
- Buck Institute for Research on Aging (US)
- University of Montana (US)
- Corresponding author
- Brem, Rachel B
- ORCID
- Venue
- G3: Genes, Genomes, Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2023-04-25
- Volume
- 13
- Issue
- 7
- ISSN
- 2160-1836 (ISSN-L)
- PMC
- PMC10320765
- OpenAlex
- W4366996754
- Cited by
- 10
- References
- 113
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 2
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- G3 Genes Genomes Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Science Foundation (1313190)
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM120430)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD094787)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- USF2, cellular senescence, DNA damage response, DNA repair, interspecies variation, Mus spretus, allele-specific expression, cis-regulatory variation, transcription factor binding sites, cytokine expression, cell cycle arrest, irradiation
- MeSH terms
- Animals, Cell Cycle, DNA Damage, Tumor Suppressor Protein p53, Cytokines, Cellular Senescence, Mice, Upstream Stimulatory Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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