RAD51 in homologous recombination-mediated DNA damage repair and genome stability: Mechanisms, regulation and implications for disease

Abstract

Homologous recombination (HR) is a high-fidelity DNA repair pathway that preserves genome stability through the accurate repair of DNA double-strand breaks. RAD51 is the central recombinase of HR and catalyzes the key processes of homology search and strand invasion through the formation of nucleoprotein filaments on single-stranded DNA. The assembly, stability, and disassembly of RAD51 filaments are tightly regulated by a complex network of mediators, cofactors, and anti-recombinases, ensuring efficient DNA repair while preventing aberrant recombination. Beyond its canonical role in HR, RAD51 also contributes to replication fork protection and replication stress responses. Dysregulation of RAD51 activity can lead to genome instability, cancer development, hereditary disorders, and cellular senescence. Conversely, elevated RAD51 expression frequently promotes therapeutic resistance in tumors. In this review, we summarize the molecular mechanisms of RAD51-mediated HR repair, discuss the regulatory pathways that control RAD51 activity and dynamics, examine its roles in genome stability and human disease, and highlight recent advances in therapeutic strategies targeting RAD51 and the HR pathway. Understanding the multifaceted functions of RAD51 will facilitate the development of more effective DNA repair-directed cancer therapies.