DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale

Firsanov, D., Zacher, M., Tian, X., Zhao, Y., Sformo, T. L., Tombline, G., Biashad, S. A., Gilman, A., Hamilton, N., Patel, A., Straight, M., Lee, M., Lu, J. Y., Haseljic, E., Williams, A., Miller, N., Zheng, Z., Perelli, L., Gurreri, E., Zhang, L., Guo, J., Korotkov, A., Volobaev, V., Zhang, Z., Heid, J., Maslov, A., Sun, S., Wu, Z., Gigas, J., Hillpot, E., Martinez, J., Ablaeva, J., Tam, L. M., Couderc, C., Hoopman, M., Fujii, S., Hayman, D. J., Liu, H., Cai, Y., Leung, A. K. L., Moritz, R., Simons, M. J. P., Nelson, C. B., Abbeglen, L. M., Schiffman, J. D., Modesti, M., Zhang, Z., Gladyshev

Department of Biology, University of Rochester, Rochester, NY, USA · biorxiv

Paper

Abstract

At over 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 kg1. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Petos Paradox2. This phenomenon has been explained by the evolution of additional tumor suppressor genes in other larger animals, supported by research on elephants demonstrating expansion of the p53 gene3-5. Here we show that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. However, analysis of DNA repair revealed that bowhead cells repair double strand breaks (DSBs) and mismatches with uniquely high efficiency and accuracy compared to other mammals. The protein CIRBP, implicated in protection from genotoxic stress, was present in very high abundance in the bowhead whale relative to other mammals. We show that CIRBP and its downstream protein RPA2, also present at high levels in bowhead cells, increase the efficiency and fidelity of DNA repair in human cells. These results indicate that rather than possessing additional tumor suppressor genes as barriers to oncogenesis, the bowhead whale relies on more accurate and efficient DNA repair to preserve genome integrity. This strategy which does not eliminate damaged cells but repairs them may be critical for the long and cancer-free lifespan of the bowhead whale.

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Research summary

The paper is relevant to longevity research as it investigates the mechanisms underlying the exceptional lifespan of the bowhead whale, particularly focusing on DNA repair and cancer resistance. These findings contribute to understanding the biological processes that may influence aging and lifespan extension. The impact score reflects that while the research presents important insights into the relationship between DNA repair mechanisms and longevity, it does not introduce a groundbreaking paradigm shift but rather adds valuable knowledge to the field.

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