Figure 7.

Model of how DNA-PK/WWP2-dependent transcription silencing at DSBs promotes NHEJ. DNA-PK and the HECT E3 ubiquitin ligase WWP2 are recruited to a DSB in a gene that is actively transcribed by RNAPII. DNA-PK effectuates WWP2-dependent K48-linked ubiquitylation of the CTD of RNAPII subunit RPB1 and the subsequent recruitment of the proteasome. The proteasome triggers RNAPII degradation directly on damaged chromatin, thereby silencing transcription of the broken gene. Finally, transcriptional silencing prevents the loss of DNA-PK and downstream NHEJ factors from DSBs, likely by protecting the NHEJ machinery from collision with the transcription machinery, thereby promoting efficient DSB repair via NHEJ.