SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging

Sirtuins enzymes are heavily implicated in senescence and aging. The regulation of sirtuin proteins is tightly controlled but how sirtuin levels are regulated during aging and how they elicit tissue-specific cellular changes are unclear. We demonstrate that SIRT7 is targeted for degradation during senescence and is regulated by E3 Ligase TRIP12. We identified transcription factor NUCKS1 interacts with SIRT7 and is recruited onto chromatin during senescence. This is mediated by SIRT7 loss and subsequent increase of NUCKS1 acetylation. NUCKS1 depletion delayed senescence leading to reduced inflammatory gene expression associated with RELA, and CEBP. In Sirt7 KO mouse and aged livers, NUCKS1 was bound at promoters and enhancers of age-related genes and these regions gain accessibility during aging. Overall, our results uncover NUCKS1 as a interactor of SIRT7 and proteosomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.