Oncometabolites as Regulators of DNA Damage Response and Repair

Dysregulation of DNA damage response and repair (DDR) contributes to oncogenesis, yet also generates the potential for targeted cancer therapies by exploiting synthetic lethal interactions. Oncometabolites, small intermediates of metabolism overproduced in certain cancers, have emerged as a new mechanism of DDR modulation through their effects on multiple DNA repair pathways. Increasing evidence suggests that oncometabolite-induced DDR defects may offer the opportunity for tumor-selective chemo- and radio-sensitization. Here we review the biology of oncometabolites and diverse mechanisms by which they impact DDR, with a focus on emerging therapeutic strategies and ongoing clinical trials targeting oncometabolite-induced DDR defects in cancer. (C) 2021 Elsevier Inc. All rights reserved.