Sch9 S6K controls DNA repair and DNA damage response efficiency in aging cells

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