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.

• PMID: 38805395
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Journal Article

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Lucca C, Ferrari E, Shubassi G, Ajazi A, Choudhary R, Bruhn C, Matafora V, Bachi A, Foiani M

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