Alternative non-homologous end joining repair: a master regulator of genomic instability in cancer

Daniele Caracciolo, Martina Montesano, Pierosandro Tagliaferri, Pierfrancesco Tassone


Genomic instability is a feature of almost all tumors but the exact mechanisms that underpin this cancer hallmark are poorly defined. Perturbation of DNA repair machinery promotes genomic instability and therefore represents an important target to design new therapeutic strategies. In this regard, the alternative non-homologous end joining (Alt-NHEJ) pathway, that is still partially understood, is considered to play a pivotal role as promoter of cancer genomic instability. Growing evidence links up-regulation of this error prone pathway with the acquisition of new genetic changes which lead to cancer onset and progression. The efficacy of poly (ADP ribose) polymerase (PARP) inhibitors has demonstrated the relevance of synthetic lethality-based approaches in cancer treatment, which might be exploited also when Alt-NHEJ plays a dominant role. In this review, we summarize recent findings which link Alt-NHEJ to the pathogenesis of different tumors, highlighting its role as genomic instability master regulator and therefore as new promising target in the precision oncology scenario.