DNA double-strand breaks (DSBs) pose a constant challenge to essential biological functions, including transcription, potentially leading to genomic instability. RNA polymerase II (RNAPII) plays a central role in detecting DNA lesions. Due to difficult-to-repair DSBs, RNAPII removal becomes challenging as it relies, among others, on multifaceted ubiquitylation mechanisms that are yet to be delineated. Our data suggests that during DSB repair, the E3 ubiquitin ligase NEDD4 as well as CRL3 complexes, albeit to a lesser extent, engage and catalyze the ubiquitylation of the elongating RNAPII, crafting a specific ubiquitin code for efficient repair. Specifically, NEDD4 is identified as the specific writer of K63-linked ubiquitin chains of S2P-RNAPII under stress as opposed to the total enzyme of RNAPII that is found to be modified mainly with K48 linkages. We find that these ligases, together with the ligase WWP2, exhibit a DNA-PK inter-dependency, driving proficient NHEJ repair and proper resolution of transcription defects caused by DSBs.