Fight Aging!

Researchers here describe a mechanism that appears to reduce DNA repair efficiency, and which can be suppressed to improve DNA repair. This is interesting, to say the least. It might be a path to determining just how much of a contribution to the pace of aging is produced by efficiency of DNA repair. The interaction between this and the finding that repeated cycles of double strand break repair induce epigenetic changes characteristic of aging is also an intriguing question. Mammalian studies sooner rather than later are called for.

The DNA-repair capacity in somatic cells is limited compared with that in germ cells. It has remained unknown whether not only lesion-type-specific, but overall repair capacities could be improved. Here we show that the DREAM repressor complex, formed by the Dp/Retinoblastoma(Rb)-like/E2F and the MuvB subcomplexes, curbs the DNA-repair capacities in somatic tissues of Caenorhabditis elegans. Mutations in the DREAM complex induce germline-like expression patterns of multiple mechanisms of DNA repair.

Consequently, DREAM mutants confer resistance to a wide range of DNA-damage types during development and aging. Similarly, inhibition of the DREAM complex in human cells boosts DNA-repair gene expression and resistance to distinct DNA-damage types. DREAM inhibition leads to decreased DNA damage and prevents photoreceptor loss in progeroid Ercc1-/- mice. We show that the DREAM complex transcriptionally represses essentially all DNA-repair systems and thus operates as a highly conserved master regulator of the somatic limitation of DNA-repair capacities.

Link: https://doi.org/10.1038/s41594-023-00942-8