Rad51B Activators

Rad51B activators consist of a diverse array of chemical compounds that, while not directly interacting with Rad51B, enhance its functional activity through the induction of cellular pathways where Rad51B's role is critical. Rucaparib, Veliparib, Olaparib, BMN 673 (Talazoparib), and the experimental compound Piparib all function as PARP inhibitors, a class of drugs that hinder the poly (ADP-ribose) polymerase family of enzymes. The inhibition of PARP leads to an accumulation of single-strand DNA breaks, which are substrates for Rad51B-mediated repair through homologous recombination. This increased DNA damage load indirectly necessitates enhanced Rad51B activity to maintain genomic stability. Similarly, DNA-damaging agents such as Trabectedin, Etoposide, Mitomycin C, Cisplatin, Camptothecin, Bleomycin, and MMS (Methyl methanesulfonate) all contribute to an increased demand for homologous recombination repair pathways. These agents induce various types of DNA lesions, such as crosslinks, double-strand breaks, or adducts, which Rad51B helps to repair accurately, ensuring cell survival and maintaining the integrity of the genetic material.

The mechanism of action for each of these activators ties back to the enhancement of Rad51B function by either increasing the number of DNA lesions that Rad51B must process or by inhibiting alternative repair pathways, thus directing the cell to rely more heavily on Rad51B. Trabectedin, for instance, binds to the minor groove of DNA and is thought to bend the DNA helix, leading to double-strand breaks that Rad51B can repair. Etoposide and Camptothecin target topoisomerases, leading to DNA breaks which then become substrates for repair by Rad51B. Mitomycin C and Cisplatin, both alkylating agents, form intrastrand and interstrand crosslinks in DNA, which are particularly reliant on homologous recombination for resolution, highlighting Rad51B's role in cellular resistance to these compounds. Bleomycin induces breaks in both strands of DNA, creating complex damage that is preferentially repaired by Rad51B-mediated pathways. Lastly, MMS causes methylation of DNA bases, leading to mismatches and lesions that are best addressed through the error-free repair mechanism involving Rad51B. Collectively, these chemicals create a cellular environment that demands heightened Rad51B activity, thereby indirectly enhancing its function in maintaining genomic stability against a backdrop of genotoxic stress.