DNA non-homologous end joining machinery (NHEJ) (NHEJ)

The DNA non-homologous end joining (NHEJ) machinery is a multi-protein complex responsible for the repair of DNA double-strand breaks (DSBs), which are among the most cytotoxic forms of genomic damage [1, 3]. This machinery operates throughout the cell cycle and functions by directly ligating broken DNA ends without requiring a homologous template, a process initiated by the binding of the Ku70/Ku80 heterodimer to the DNA lesion [1]. The Ku complex then recruits the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming a holoenzyme that facilitates the recruitment of processing factors like Artemis and the ligation complex consisting of XRCC4, XLF, and DNA ligase IV [3]. In the context of oncology, the NHEJ machinery is a high-priority therapeutic target; inhibiting its components can prevent cancer cells from repairing damage caused by ionizing radiation or DNA-damaging chemotherapy, thereby promoting mitotic catastrophe and apoptosis [2]. Several small-molecule inhibitors targeting DNA-PKcs, such as Peposertib and Nedisertib, are currently undergoing clinical evaluation as radiosensitizers and chemosensitizers [2, 4]. However, therapeutic targeting of NHEJ presents challenges, as the pathway is also essential for V(D)J recombination during lymphocyte development, meaning systemic inhibition can lead to severe immunodeficiency and hematological toxicities [2].

Other names

Non-homologous end joiningNHEJ pathwayCanonical non-homologous end joiningC-NHEJ

Inhibition of the NHEJ machinery, primarily through the targeting of DNA-PKcs or DNA ligase IV, prevents the repair of DNA double-strand breaks. This leads to the accumulation of lethal DNA lesions, sensitizing cells to exogenous DNA-damaging agents like radiation and topoisomerase inhibitors [2].