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

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. In spite of its very large number of cells, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox. This has been explained by the evolution of additional tumor suppressor genes in larger animals, which is supported by research on elephants demonstrating expansion of the p53 gene. However, we show here that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. Instead, analysis of DNA repair revealed that bowhead cells repair double-strand breaks with uniquely high efficiency and accuracy compared to other mammals. Further, we identified two proteins, CIRBP and RPA2, that are present at high levels in bowhead fibroblasts and increase the efficiency and fidelity of DNA repair in human cells. These results suggest 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 that does not eliminate cells but repairs them may be critical for the long and cancer-free lifespan of the bowhead whale. Our work demonstrates the value of studying long-lived organisms in identifying novel longevity mechanisms and their potential for translation to humans.

Rapid evolution of genes with anti-cancer functions during the origins of large bodies and cancer resistance in elephants

“…Among the positively selected and rapidly evolving genes, for example, are RIF1 , which cooperates with TP53BP1 to promote DNA repair by non-homologous end joining (NHEJ) in the G 1 and S phases of the cell cycle (Escribano-Díaz et al, 2013; Feng et al, 2013; Virgilio et al, 2013), the multifunctional exonuclease EXO1 , which is involved in DNA damage checkpoint progression, mismatch repair (MMR), translesion DNA synthesis (TLS), nucleotide excision repair (NER), and limits end resection of double-strand breaks thereby facilitating repair via error-free homologous recombination (HR) rather than error-prone NHEJ (Keijzers et al, 2018; Tomimatsu et al, 2017), MLH1 , part of PMS2 MMR complex that generates single-strand breaks near the mismatch and entry points for EXO1 to degrade the strand containing the mismatch (Kadyrov et al, 2006; Kansikas et al, 2011; Sacho et al, 2008), NEK4 , which regulates a unique ATM/ATR-independent DNA damage checkpoint and the induction of replicative senescence in response to double-stranded (DSB) DNA damage (Chen et al, 2011; Tomimatsu et al, 2017), KAT5 , an acetyltransferase that plays an essential role in DNA damage repair by acetylating and activating ATM and the canonical DSB repair pathway (Sun et al, 2005)and SAMHD1 which promotes DNA end resection to facilitate DSB repair by HR (Daddacha et al, 2017; Kapoor-Vazirani et al, 2022). Similarly, long-lived and cancer-resistant Bowhead whales, which have a maximum lifespan of over 200 years (George et al, 1999), have evolved cells that repair double-strand breaks with high efficiency and accuracy compared to many other mammals (Firsanov et al, 2023), suggesting that the evolution of DNA damage repair genes may be a common route to evolve cancer resistance.…”

The stem cell zoo for comparative studies of developmental tempo

“…These findings are consistent with the role of biochemical kinetics as regulators of developmental tempo. Species-specific mechanisms for extended lifespan are also reported, including the uniquely high efficiency and accuracy in DNA repair of the long-lived bowhead whale [50] . This is in line with the observations that somatic mutation rates are inversely correlated with lifespan across species [51] .…”

Kimura’s Theory of Non-Adaptive Radiation and Peto’s Paradox: A Missing Link?

“…The bowhead whale thus benefits from a long life span because its cells are more proficient at repairing DNA damage. The study identified two proteins (CIRBP and RPA2) that are present at high levels in fibroblasts and are known to increase the fidelity and efficiency of DNA double-strand break (DSB) repair [ 34 ].…”