Sch9S6K controls DNA repair and DNA damage response efficiency in aging cells

Abstract

Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1^ATR DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1^ATR. We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1^AMPK rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9^S6K axis restores NER and enhances DDR by tuning PP2A activity, specifically in aging cells. Age-related repair deficiency depends on Snf1^AMPK-mediated phosphorylation of Sch9^S6K on Ser160 and Ser163. PP2A activity in old cells is detrimental for DDR and influences NER by modulating Snf1^AMPK and Sch9^S6K. Hence, the DDR and repair pathways in aging cells are influenced by the metabolic tuning of opposing AMPK and TORC1 networks and by PP2A activity. Specific Sch9^S6K phospho-isoforms control DDR and NER efficiency, specifically during aging.

Keywords: ATR/Mec1; CP: Molecular biology; DDR; DNA repair; PP2A; Rad53; Sch9; Snf1; TORC1; UV lesions; aging.