Amodiaquine ameliorates stress-induced premature cellular senescence via promoting SIRT1-mediated HR repair.

DNA damage is considered to be a potentially unifying driver of ageing, and the stalling of DNA damage repair accelerates the cellular senescence. However, augmenting DNA repair has remained a great challenge due to the intricate repair mechanisms specific for multiple types of lesions. Herein, we miniaturized our modified detecting system for homologous recombination (HR) into a 96-well-based platform and performed a high-throughput chemical screen for FDA-approved drugs. We uncovered that amodiaquine could significantly augment HR repair at the noncytotoxic concentration. Further experiments demonstrated that amodiaquine remarkably suppressed stress-induced premature cellular senescence (SIPS), as evidenced by senescence-associated beta-galactosidase (SA-β-gal) staining or senescence-related markers p21 and p16, and the expression of several cytokines. Mechanistic studies revealed that the stimulation of HR repair by amodiaquine might be mostly attributable to the promotion of SIRT1 at the transcriptional level. Additionally, SIRT1 depletion abolished the amodiaquine-mediated effects on DNA repair and cellular senescence, indicating that amodiaquine delayed the onset of SIPS via a SIRT1-dependent pathway. Taken together, this experimental approach paved the way for the identification of compounds that augment HR activity, which could help to underscore the therapeutic potential of targeting DNA repair for treating aging-related diseases.