Novel Insights into RAD52’s Structure, Function, and Druggability for Synthetic Lethality and Innovative Anticancer Therapies

SIMPLE SUMMARY: Human RAD52 is a non-essential DNA/RNA-binding protein thought to be involved in many DNA repair mechanisms. Initially regarded as having a major role only in error-prone backup DNA repair mechanisms, RAD52 has recently gained attention because its inhibition induces synthetic lethality in cancer cells with an inactivated homologous recombination pathway (for error-free double-strand-break repair). RAD52 is thus a potential target to overcome resistance and unwanted side effects. Unfortunately, researchers still lack detailed structural and mechanistic information on RAD52 and have identified only a limited number of inhibitors, none of which are in the preclinical phase. This review summarizes the current knowledge on RAD52, highlighting the potential of its inhibition. This review also discusses the critical gaps in knowledge and sets out future directions for effective campaigns to discover RAD52 inhibitors. ABSTRACT: In recent years, the RAD52 protein has been highlighted as a mediator of many DNA repair mechanisms. While RAD52 was initially considered to be a non-essential auxiliary factor, its inhibition has more recently been demonstrated to be synthetically lethal in cancer cells bearing mutations and inactivation of specific intracellular pathways, such as homologous recombination. RAD52 is now recognized as a novel and critical pharmacological target. In this review, we comprehensively describe the available structural and functional information on RAD52. The review highlights the pathways in which RAD52 is involved and the approaches to RAD52 inhibition. We discuss the multifaceted role of this protein, which has a complex, dynamic, and functional 3D superstructural arrangement. This complexity reinforces the need to further investigate and characterize RAD52 to solve a challenging mechanistic puzzle and pave the way for a robust drug discovery campaign.