The study by Tilgner et al.1 investigates the role of non-homologous end joining (NHEJ) in reprogramming of human somatic cells to induced pluripotent stem cells and in regulation of their differentiation. NHEJ is the major double-strand break (DSB) repair pathway in mammalian cells.2 It is a highly coordinated process relying on a number of essential proteins, such as DNA ligase IV, which is required for the final ‘end processing' step.3 Mutations in DNA ligase IV lead to the LIG4 syndrome characterised by growth defects, microcephaly, impaired haematopoiesis, immunodeficiency and increased susceptibility to leukemia. Complete loss of DNA ligase IV in the mouse leads to embryonic lethality, suggesting that mutations in the LIG4 syndrome are generally hypomorphic.