Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection

Early after infection, the retroviral RNA genome is reverse transcribed to generate a linear cDNA copy, then that copy is integrated into a chromosome of the host cell. We report that unintegrated viral cDNA is a substrate fo r the host cell non-homologous DNA end joining (NHEJ) pathway, which normal ly repairs cellular double-strand breaks by end ligation, NHEJ activity was found to be required for an end-ligation reaction that circularizes a port ion of the unintegrated viral cDNA in infected tells, Consistent with this, the NHEJ proteins Ku70 and Ku80 were found to be bound to purified retrovi ral replication intermediates, Cells defective in NHEJ are known to undergo apoptosis in response to retroviral infection, a response that we show req uires reverse transcription to form the cDNA genome but not subsequent inte gration, We propose that the double-strand ends present in unintegrated cDN A promote apoptosis, as is known to be the case for chromosomal double-stra nd breaks, and cDNA circularization removes the pro-apoptotic signal.