DNA repair and anti-cancer mechanisms in the long-lived bowhead whale

作者：Denis Firsanov, Max Zacher, Xiao Tian, Todd L. Sformo, Yang Zhao, Greg Tombline, J. Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, A. Korotkov, Valentin P. Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alex Maslov, Shixiang Sun, Zhihao Wu, Jonathan Gigas, Eric Hillpot, John Jairo Briceño Martínez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ena Haseljic, Avnee Patel, Maggie E. Straight, N. R. Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael Hoopman, Robert L. Moritz, Shingo Fujii, Dan J. Hayman, Hongrui Liu, Yuxuan Cai, Anthony K. L. Leung, Mirre J. P. Simons, Zhengdong D. Zhang, Christopher B. Nelson, Lisa M. Abegglen, Joshua D. Schiffman, Vadim N. Gladyshev, Mauro Modesti, Giannicola Genovese, Jan Vijg, Andrei Seluanov, Vera Gorbunova · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.05.07.539748 · 被引用次数：26 · 研究领域：Cancer-related Molecular Pathways、Epigenetics and DNA Methylation、Animal Genetics and Reproduction

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 kg 1 . Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto’s Paradox 2 . 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 gene 3–5 . 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...