Bowhead whales are the second-largest animal on Earth, and their lifespan can exceed 200 years. This long life and large body mass should result in the accumulation of large numbers of DNA mutations; however, the bowhead whale is not highly prone to cancer. In an effort to understand this conundrum, Firsanov, Zacher et al. investigated the molecular basis for the bowhead whale’s cancer resistance. Surprisingly, they determined that bowhead whale fibroblasts typically require fewer genetic changes for cells to become malignant than human primary fibroblasts. Yet whole-genome sequencing results indicated that bowhead whale tumor cells have a lower frequency of de novo somatic single-nucleotide variants than human and mouse tumor cells, as well as reduced numbers of both small insertion–deletion events and large structural variants. The team then assessed the efficiency of DNA repair pathways in several mammalian species, with whale fibroblasts exhibiting significantly higher frequencies of both non-homologous end-joining and homologous recombination than other species studied. Comparing the expression of DNA repair proteins across mammals using immunoblot, quantitative mass spectrometry and transcriptome sequencing revealed that cold-inducible RNA-binding protein (CIRBP) was highly expressed in bowhead whale cells, but not in those of other mammals investigated. Whereas overexpression of CIRBP increased successful non-homologous end-joining and homologous recombination repair, its depletion via small-interfering RNA significantly reduced the efficiency of those repair pathways and increased DNA deletions in bowhead whale cells. CIRBP was found to be recruited to DNA double-strand breaks, where it facilitates binding of DNA repair proteins and protects DNA ends from resection. Finally, the team showed that overexpression of human and bowhead whale CIRBP in Drosophila resulted in an extension of lifespan. These results highlight the importance of CIRBP in mediating efficient DNA repair in bowhead whales and potentially provide an avenue for exploring routes to prevent cancer and increase the human lifespan.
Original reference: Nature https://doi.org/10.1038/s41586-025-09694-5 (2025)
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