Evidence for improved DNA repair in long-lived bowhead whale

Denis Firsanov^#¹, Max Zacher^#¹, Xiao Tian¹, Todd L Sformo², Yang Zhao¹, Gregory Tombline¹, J Yuyang Lu¹, Zhizhong Zheng¹, Luigi Perelli³, Enrico Gurreri⁴, Li Zhang⁴, Jing Guo¹, Anatoly Korotkov¹, Valentin Volobaev¹, Seyed Ali Biashad¹, Zhihui Zhang¹, Johanna Heid⁵, Alexander Y Maslov⁵, Shixiang Sun⁵, Zhuoer Wu¹, Jonathan Gigas¹, Eric C Hillpot¹, John C Martinez¹, Minseon Lee¹, Alyssa Williams¹, Abbey Gilman¹, Nicholas Hamilton¹, Ekaterina Strelkova¹, Ena Haseljic¹, Avnee Patel¹, Maggie E Straight¹, Nalani Miller¹, Julia Ablaeva¹, Lok Ming Tam¹, Chloé Couderc¹, Michael R Hoopmann⁶, Robert L Moritz⁶, Shingo Fujii⁷, Amandine Pelletier⁷, Dan J Hayman⁸, Hongrui Liu^{9

10}, Yuxuan Cai⁹, Anthony K L Leung^{9

11

12

13}, Zhengdong Zhang⁵, C Bradley Nelson¹⁴, Lisa M Abegglen^{15

16}, Joshua D Schiffman^{15

16}, Vadim N Gladyshev¹⁷, Carlo C Maley^{18

19}, Mauro Modesti⁷, Giannicola Genovese^{4

20

21

22}, Mirre J P Simons⁸, Jan Vijg²³, Andrei Seluanov^{24

25}, Vera Gorbunova^{26

27}

Affiliations

¹ Department of Biology, University of Rochester, Rochester, NY, USA.
² North Slope Borough Department of Wildlife Management, Utqiaġvik (Barrow), AK, USA.
³ Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
⁶ Institute for Systems Biology, Seattle, WA, USA.
⁷ Cancer Research Center of Marseille, Department of Genome Integrity, CNRS UMR7258, Inserm U1068, Institut Paoli-Calmettes, Aix Marseille University, Marseille, France.
⁸ School of Biosciences, University of Sheffield, Sheffield, UK.
⁹ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Cross-Disciplinary Graduate Program in Biomedical Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹ McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁵ Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁶ Peel Therapeutics Inc., Salt Lake City, UT, USA.
¹⁷ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Arizona Cancer Evolution Center, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
¹⁹ School of Life Sciences, Arizona State University, Tempe, AZ, USA.
²⁰ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²¹ TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²² David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²³ Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. jan.vijg@einsteinmed.edu.
²⁴ Department of Biology, University of Rochester, Rochester, NY, USA. andrei.seluanov@rochester.edu.
²⁵ Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. andrei.seluanov@rochester.edu.
²⁶ Department of Biology, University of Rochester, Rochester, NY, USA. vera.gorbunova@rochester.edu.
²⁷ Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. vera.gorbunova@rochester.edu.

^# Contributed equally.

PMID: 41162698
DOI: 10.1038/s41586-025-09694-5

Free article

Evidence for improved DNA repair in long-lived bowhead whale

Denis Firsanov et al. Nature. 2025.

Free article

. 2025 Oct 29.

doi: 10.1038/s41586-025-09694-5. Online ahead of print.

Authors

Affiliations

¹ Department of Biology, University of Rochester, Rochester, NY, USA.
² North Slope Borough Department of Wildlife Management, Utqiaġvik (Barrow), AK, USA.
³ Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
⁶ Institute for Systems Biology, Seattle, WA, USA.
⁷ Cancer Research Center of Marseille, Department of Genome Integrity, CNRS UMR7258, Inserm U1068, Institut Paoli-Calmettes, Aix Marseille University, Marseille, France.
⁸ School of Biosciences, University of Sheffield, Sheffield, UK.
⁹ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
¹⁰ Cross-Disciplinary Graduate Program in Biomedical Sciences, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹ McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁵ Department of Pediatrics and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹⁶ Peel Therapeutics Inc., Salt Lake City, UT, USA.
¹⁷ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Arizona Cancer Evolution Center, Biodesign Institute, Arizona State University, Tempe, AZ, USA.
¹⁹ School of Life Sciences, Arizona State University, Tempe, AZ, USA.
²⁰ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²¹ TRACTION Platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²² David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²³ Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. jan.vijg@einsteinmed.edu.
²⁴ Department of Biology, University of Rochester, Rochester, NY, USA. andrei.seluanov@rochester.edu.
²⁵ Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. andrei.seluanov@rochester.edu.
²⁶ Department of Biology, University of Rochester, Rochester, NY, USA. vera.gorbunova@rochester.edu.
²⁷ Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA. vera.gorbunova@rochester.edu.

^# Contributed equally.

PMID: 41162698
DOI: 10.1038/s41586-025-09694-5

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 Earth¹, 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 paradox². 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^3-5, 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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Conflict of interest statement

Competing interests: VG is a consultant for DoNotAge, MatrixBio, Elysium, Bionic Health, WndrHealth and GenFlow Bio. JV and AYM are founders and shareholders of Singulomics Corp and Mutagentech Inc. Other authors declare no competing interests.

References

1. Tacutu, R. et al. Human Ageing Genomic Resources: new and updated databases. Nucleic Acids Res. 46, D1083–D1090 (2018). - PubMed - DOI
1. Peto, R. in The Origins of Human Cancer, Vol. 4 (eds Hiatt, H., Watson, J. & Winsten, J.) 1403–1428 (Cold Spring Harbor Laboratory, 1977).
1. TEK & Bowhead Life History and Longevity. The North Slope Borough https://www.north-slope.org/departments/wildlife-management/studies-rese... (2025).
1. Rosa, C. et al. Age estimates based on aspartic acid racemization for bowhead whales (Balaena mysticetus) harvested in 1998–2000 and the relationship between racemization rate and body temperature. Mar. Mamm. Sci. 29, 424–445 (2013). - DOI
1. George, J. C. & Bockstoce, J. R. Two historical weapon fragments as an aid to estimating the longevity and movements of bowhead whales. Polar Biol. 31, 751–754 (2008). - DOI

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Evidence for improved DNA repair in long-lived bowhead whale

Affiliations

Evidence for improved DNA repair in long-lived bowhead whale

Authors

Affiliations

Abstract

Conflict of interest statement

References

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