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

Abstract

Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12. We identified the transcription factor nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) as an interactor of SIRT7 and found NUCKS1 recruitment onto chromatin during senescence mediated by SIRT7 loss, correlating with increased NUCKS1 acetylation. NUCKS1 depletion delayed senescence, leading to reduced inflammatory gene expression associated with transcription factors RELA and CEBPβ. In Sirt7 knockout and aged mouse livers, NUCKS1 was bound at the promoters and enhancers of age-related genes, and these regulatory regions gained accessibility during aging. Overall, our results uncover NUCKS1 as an interactor of SIRT7 and indicate that proteasomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.