Updated project metadata. Radiotherapy is one of the mainstays for the treatment of hepatocellular carcinoma (HCC); however, a substantial fraction of HCC patients develops radioresistance and eventually suffer from tumour progression or relapse, a major impediment to the use of radiotherapy. One of the main goals in HCC management is to elucidate the mechanisms underlying radioresistance and identify novel therapeutic targets to improve the patients' prognosis. In this study, we report a DNA repair enhancer, human positive cofactor 4 (PC4), that promotes NHEJ-based DNA repair and renders HCC cells resistant to radiation. Mechanistically, PC4 interacts with PARP1 and directs Ku complex PARylation, resulting in successful recruitment of the Ku complex to damaged chromatin and increasing the efficiency of NHEJ repair. Clinically, PC4 is highly expressed in tumour tissues, which is correlated with poor prognosis in HCC patients. Taken together, our data suggest that PC4 is a DNA repair driver that can be targeted to radiosensitize HCC.