Naked Mole Rats Repair DNA Damage More Efficiently than Mice

Naked mole rats live nine times longer than other, similarly sized rodents. They are also near immune to cancer. Researchers are mining the biochemistry of this species in search of mechanisms that might inform the development of ways to treat cancer or influence the processes of degenerative aging. Cancer is a consequence of mutation in nuclear DNA, and the consensus of the majority of the research community is that this random mutational damage, stem and progenitor cells, is a meaningful cause of aging. Thus should we expect naked mole rats to have highly effective DNA repair in comparison to short-lived rodents? It seems to be the case that they do.

Aging and cancer are accompanied by the accumulation of mutations in the genome, genomic instability and dysregulation of transcription patterns. DNA repair systems have evolved to counteract genomic instability. However, whether long-lived and cancer-resistant animal species have more efficient DNA repair is unclear. The naked mole rat (NMR), Heterocephalus glaber, is the longest-lived rodent with the maximum lifespan of 32 years, which is almost ten times longer than a house mouse. Furthermore, NMRs are resistant to cancer with spontaneous tumors being extremely rare.

NMRs evolved a variety of adaptations that may contribute to longevity and cancer resistance. Some of these adaptations may promote genome and proteome stability and increase resistance to stress. NMR proteins involved in redox processes are more resistant to denaturing agents and are able to maintain function under oxidative stress. High accuracy of translation process, increased level of expression of key chaperones and more active proteasomes help to maintain a pool of functional proteins.

Transcriptome analyses by RNA sequencing showed that several genes involved in DNA repair are up-regulated in H. glaber cells. However, transcript levels do not always unambiguously reflect the level of protein expression and activity. NMR cells were found to be more resistant than mouse cells to a variety of stressors. Cell survival under stress is a function of the repair capacity, cell cycle checkpoints, and apoptotic responses. Therefore, NMRs may have more efficient base excision repair (BER) and nucleotide excision repair (NER) systems that protect the cells from mutations coupled with heightened stress responses.

Here we performed the analysis of BER and NER systems in NMR and mouse fibroblasts in response to UVC-light exposure. We evaluated post-irradiation changes in mRNA transcription of several key reparative proteins and measured the activities of the key BER and NER enzymes. Our results suggest that NMR has more efficient BER and NER systems than the short-lived and tumor-prone mouse, which may contribute to longevity and cancer resistance of this species.

Link: https://doi.org/10.18632/aging.101482

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