Sch9S6K controls DNA repair and DNA damage response efficiency in aging cells
Chiara Lucca,
Elisa Ferrari,
Ghadeer Shubassi,
Arta Ajazi,
Ramveer Choudhary,
Christopher Bruhn,
Vittoria Matafora,
Angela Bachi,
Marco Foiani
Affiliations
Chiara Lucca
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Elisa Ferrari
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Corresponding author
Ghadeer Shubassi
AtomVie Global Radiopharma Inc., 1280 Main Street W NRB-A316, Hamilton, ON L8S-4K1, Canada
Arta Ajazi
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Ramveer Choudhary
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Christopher Bruhn
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Vittoria Matafora
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Angela Bachi
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy
Marco Foiani
IFOM ETS – The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy; Istituto di Genetica Molecolare, CNR, Pavia, Italy; Corresponding author
Summary: Survival from UV-induced DNA lesions relies on nucleotide excision repair (NER) and the Mec1ATR DNA damage response (DDR). We study DDR and NER in aging cells and find that old cells struggle to repair DNA and activate Mec1ATR. We employ pharmacological and genetic approaches to rescue DDR and NER during aging. Conditions activating Snf1AMPK rescue DDR functionality, but not NER, while inhibition of the TORC1-Sch9S6K axis restores NER and enhances DDR by tuning PP2A activity, specifically in aging cells. Age-related repair deficiency depends on Snf1AMPK-mediated phosphorylation of Sch9S6K on Ser160 and Ser163. PP2A activity in old cells is detrimental for DDR and influences NER by modulating Snf1AMPK and Sch9S6K. 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 Sch9S6K phospho-isoforms control DDR and NER efficiency, specifically during aging.
