Recent Developments Using Small Molecules to Target RAD51: How to Best Modulate RAD51 for Anticancer Therapy?

Abstract

Homologous recombination (HR) is an evolutionarily conserved DNA repair process. Overexpression of the key HR protein RAD51 is a common feature of malignant cells. RAD51 plays two distinct genome-stabilizing roles, including HR-mediated repair of double-strand breaks (DSBs) and the promotion of replication fork stability during replication stress. Because upregulation of RAD51 in cancer cells can promote tumor resistance to DNA-damaging oncologic therapies, we and others have worked to develop cancer therapeutics that target various aspects of RAD51 protein function. Herein, we provide an overview of recent developments in this field, together with our perspectives on the challenges associated with these evolving anticancer strategies.

RADX Promotes Genome Stability and Modulates Chemosensitivity by Regulating RAD51 at Replication Forks

“…Low activity can yield genome instability through defects in fork protection and HDR, but it also improves the cell killing by chemotherapeutics and PARP inhibitors (Budke et al, 2016; Quiros et al, 2011). On the other hand, RAD51 overexpression causes genome instability (Klein, 2008; Richardson et al, 2004), and RAD51 is frequently overexpressed in cancers (Klein, 2008).…”

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

“…Second, inhibiting the central, but not the initial step in HR, after the DSB is committed to be repaired through a homology directed mechanism prevents it from repair by NHEJ. Finally, RAD51 overexpression has been observed in a range of different cancers, and the associated resistance to radiation and chemotherapy was overcome by reduction in RAD51 expression (reviewed in (Klein, 2008) and (Budke et al, 2016)).…”

O-Glcnac Glycosylation of Rad51 Plays an Important Role in Promoting Colorectal Cancer Cell Invasion

“…Rad51 overexpression leads to the accumulation of abnormal karyotypes and gene mutations, which are closely related to carcinogenesis and drug resistance [16]. Studies have shown that, such as breast cancer, pancreatic cancer and other tumors overexpressed Rad51 protein, positively correlated to tumor histological grade and stage [17,18]. In addition, domestic and foreign researchers also found that gene polymorphism of Rad51 recognized as the risk factor of CRC carcinogenesis.…”