Non-homologous end joining pathway (NHEJ)

The Non-homologous end joining (NHEJ) pathway is a fundamental DNA repair mechanism responsible for ligating DNA double-strand breaks (DSBs) without the need for a homologous template (Davis & Chen, 2013). It operates throughout the cell cycle but is particularly dominant in the G0 and G1 phases, involving a core set of proteins including the Ku70/Ku80 heterodimer, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and the DNA ligase IV complex (Mohiuddin & Kang, 2019). In the context of cancer therapy, NHEJ is a high-priority target because many conventional treatments, such as radiotherapy and certain chemotherapies, work by inducing DSBs (Zenke et al., 2020). By pharmacologically inhibiting key NHEJ components like DNA-PKcs, clinicians can prevent cancer cells from repairing this damage, thereby enhancing the efficacy of DNA-damaging agents (Pannunzio et al., 2018). However, since NHEJ is also required for V(D)J recombination in developing lymphocytes, its inhibition can lead to significant side effects, including lymphopenia and increased sensitivity of normal tissues to radiation (Woodbine et al., 2014).

Other names

Classical non-homologous end joiningC-NHEJDNA double-strand break repair via NHEJ

Inhibition of key enzymes within the pathway, such as DNA-dependent protein kinase catalytic subunit (DNA-PKcs) or DNA ligase IV, to prevent the repair of DNA double-strand breaks and sensitize cells to DNA-damaging therapies.