Evidence for improved DNA repair in long-lived bowhead whale

Abstract

At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto’s paradox. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. However, bowhead whale cells exhibited enhanced DNA double-strand break repair capacity and fidelity, and lower mutation rates than cells of other mammals. We found the cold-inducible RNA-binding protein CIRBP to be highly expressed in bowhead fibroblasts and tissues. Bowhead whale CIRBP enhanced both non-homologous end joining and homologous recombination repair in human cells, reduced micronuclei formation, promoted DNA end protection, and stimulated end joining in vitro. CIRBP overexpression in Drosophila extended lifespan and improved resistance to irradiation. These findings provide evidence supporting the hypothesis that, rather than relying on additional tumour suppressor genes to prevent oncogenesis, the bowhead whale maintains genome integrity through enhanced DNA repair. This strategy, which does not eliminate damaged cells but faithfully repairs them, may be contributing to the exceptional longevity and low cancer incidence in the bowhead whale.

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Item Type:	Article
Authors/Creators:	Firsanov, D. Zacher, M. https://orcid.org/0000-0003-0377-7221 Tian, X. Sformo, T.L. https://orcid.org/0000-0003-4833-2007 Zhao, Y. https://orcid.org/0000-0002-8703-3678 Tombline, G. Lu, J.Y. https://orcid.org/0000-0003-3170-5655 Zheng, Z. Perelli, L. https://orcid.org/0000-0001-7320-8193 Gurreri, E. https://orcid.org/0000-0002-7752-4641 Zhang, L. https://orcid.org/0000-0002-7750-6427 Guo, J. https://orcid.org/0000-0003-4154-1885 Korotkov, A. Volobaev, V. https://orcid.org/0000-0001-7355-9882 Biashad, S.A. Zhang, Z. https://orcid.org/0000-0003-0635-6297 Heid, J. https://orcid.org/0000-0001-7760-5217 Maslov, A.Y. https://orcid.org/0000-0001-5402-8891 Sun, S. https://orcid.org/0000-0001-5499-2963 Wu, Z. https://orcid.org/0009-0000-4694-6668 Gigas, J. Hillpot, E.C. Martinez, J.C. https://orcid.org/0000-0003-0040-8519 Lee, M. Williams, A. Gilman, A. Hamilton, N. Strelkova, E. Haseljic, E. Patel, A. Straight, M.E. https://orcid.org/0000-0001-7916-0282 Miller, N. Ablaeva, J. https://orcid.org/0000-0002-0938-2629 Tam, L.M. https://orcid.org/0000-0002-6211-6880 Couderc, C. Hoopmann, M.R. https://orcid.org/0000-0001-7029-7792 Moritz, R.L. https://orcid.org/0000-0002-3216-9447 Fujii, S. https://orcid.org/0000-0002-5800-7235 Pelletier, A. Hayman, D.J. https://orcid.org/0000-0001-9125-1945 Liu, H. https://orcid.org/0000-0002-6274-5951 Cai, Y. Leung, A.K.L. https://orcid.org/0000-0001-5569-4036 Zhang, Z. Nelson, C.B. https://orcid.org/0009-0007-8775-1809 Abegglen, L.M. https://orcid.org/0000-0003-3607-3001 Schiffman, J.D. https://orcid.org/0000-0002-6968-7694 Gladyshev, V.N. https://orcid.org/0000-0002-0372-7016 Maley, C.C. https://orcid.org/0000-0002-0745-7076 Modesti, M. https://orcid.org/0000-0002-4964-331X Genovese, G. https://orcid.org/0000-0003-1392-9954 Simons, M.J.P. https://orcid.org/0000-0001-7406-7708 Vijg, J. https://orcid.org/0000-0002-8457-9595 Seluanov, A. Gorbunova, V. https://orcid.org/0000-0001-8979-0333
Copyright, Publisher and Additional Information:	© The Author(s) 2025. This article is licensed under a Creative Commons Attribution Non Commercial-No Derivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Keywords:	Cancer models; Double-strand DNA breaks; Non-homologous-end joining; Senescence
Dates:	Submitted: 18 April 2023 Accepted: 30 September 2025 Published (online): 29 October 2025 Published: 29 October 2025
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield)
Date Deposited:	05 Nov 2025 16:14
Last Modified:	05 Nov 2025 16:14
Status:	Published online
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41586-025-09694-5
Related URLs:	PubMed URL Software or Code
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:234026

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Evidence for improved DNA repair in long-lived bowhead whale

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