Evolutionary mutation in cGAS enhances naked mole-rat DNA repair

The secret to the naked mole-rats' extraordinarily long life may lie in subtle changes to just four amino acids, researchers report. According to a new study, evolutionary mutations in cGAS – an enzyme in the innate immune system that senses DNA to trigger immune responses – may enhance the animal's ability to repair aging-related genetic damage, whereas in other species, such as mice and humans, cGAS can suppress DNA repair.

Wrinkled and unassuming though they appear, the naked mole-rat (Heterocephalus glaber) is an exceptionally long-lived rodent, with a maximum life span of nearly 40 years – roughly 10 times longer than similarly sized species. Moreover, the creatures' genetic makeup is surprisingly closer to humans than to mice, which makes it a valuable model for studying the molecular mechanisms underlying the species' longevity.

One key aspect of long life is genome stability. However, the ways naked mole-rats maintain DNA integrity, particularly through repair mechanisms, remain poorly understood. Homologous recombination (HR) is a critical DNA repair pathway, and defects in HR are linked to premature aging. In humans and mice, the DNA sensor cGAS (cyclic guanosine monophosphate–adenosine monophosphate synthase) can suppress HR repair, potentially promoting cancer and shortening lifespan.

Yu Chen and colleagues investigated whether cGAS similarly inhibits HR in long-lived naked mole-rats. Chen et al. found that, in naked mole-rats, four specific amino acid substitutions in mole-rat cGAS reduce ubiquitination and degradation, allowing the protein to persist for longer and at higher levels after DNA damage. This increased abundance strengthens interactions with key repair factors, FANCI and RAD50, thereby boosting HR repair.

When cGAS was depleted from naked mole-rat cells, DNA damage accumulated. The authors further showed that fruit flies engineered to express human cGAS containing the four naked mole-rat–specific mutations lived longer than flies expressing unaltered human cGAS. The findings suggest that these specific evolutionary amino acid mutations in naked mole-rat cGAS not only enhance DNA repair but may also contribute directly to the extraordinary longevity of the species.

"The findings from Chen et al. describe an unexpected role for naked mole-rat cGAS in the nucleus that influences longevity, write John Martinez and colleagues in a related Perspective. "Further research will be required to establish the roles that cGAS may play in the nucleus in other organisms, both short- and long-lived, but the answer may be substantially more complex than originally predicted."