TP53 and cancer: As a novel component of the DNA-PK complex and regulator of DNA-PK stability and activity (Fig. 5c), LRF represents an attractive biomarker with important therapeutic implications since its downregulation might serve to identify those tumours that are particularly dependent on NHEJ activity, such as for instance a subset of p53-null cancers, towards therapeutic treatments based on genotoxic agents, radiation, or PARP inhibitors following the synthetic lethality paradigm.