DNAH5 Activators

DNA pol θ Activators, a class of chemical compounds, play a significant role in indirectly enhancing the functional activity of DNA polymerase theta (DNA pol θ), encoded by the POLQ gene, particularly in DNA repair processes. This set of activators primarily influences DNA pol θ by modulating various DNA repair pathways, thereby increasing the protein's involvement in alternative non-homologous end joining (alt-NHEJ). For example, Olaparib, Rucaparib, Niraparib, Veliparib, and Talazoparib, all PARP inhibitors, significantly enhance DNA pol θ's activity. They do this by inhibiting the homologous recombination (HR) pathway, shifting the cellular reliance to alt-NHEJ where DNA pol θ is crucial. Similarly, Mirin, an MRE11 inhibitor, and NU7441, a DNA-PKcs inhibitor, alter the DNA repair landscape by inhibiting key players in HR and classical NHEJ, respectively. This shift in DNA repair mechanisms increases the dependency on DNA pol θ for effective DNA repair, particularly under conditions of genotoxic stress.

Moreover, ATM inhibitors like KU-55933 and its derivative KU-60019, as well as ATR inhibitors such as AZD6738 and VE-821, play a pivotal role in modulating the DNA damage response. By influencing these pathways, they indirectly promote the activity of DNA pol θ in DNA repair. The WEE1 inhibitor MK-1775 also contributes by accelerating cell cycle progression, which in turn can increase the demand for DNA pol θ's function in repairing DNA during replicative stress. Collectively, these DNA pol θ Activators, through their targeted effects on various DNA repair pathways, essentially create a cellular environment where the functional activity of DNA pol θ is critically heightened. This enhancement is crucial for maintaining genomic stability, particularly in contexts where the usual high-fidelity repair mechanisms are inhibited or compromised.