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Role of the non‐homologous DNA end joining pathway in the early steps of retroviral infection
Author(s) -
Li Ling,
Olvera Jennifer M.,
Yoder Kristine E.,
Mitchell Richard S.,
Butler Scott L.,
Lieber Michael,
Martin Sandra L.,
Bushman Frederic D.
Publication year - 2001
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/20.12.3272
Subject(s) - biology , complementary dna , ku70 , ku80 , non homologous end joining , reverse transcriptase , dna , microbiology and biotechnology , homologous recombination , rna , genetics , dna repair , gene , dna binding protein , transcription factor
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 for the host cell non‐homologous DNA end joining (NHEJ) pathway, which normally repairs cellular double‐strand breaks by end ligation. NHEJ activity was found to be required for an end‐ligation reaction that circularizes a portion of the unintegrated viral cDNA in infected cells. Consistent with this, the NHEJ proteins Ku70 and Ku80 were found to be bound to purified retroviral replication intermediates. Cells defective in NHEJ are known to undergo apoptosis in response to retroviral infection, a response that we show requires reverse transcription to form the cDNA genome but not subsequent integration. We propose that the double‐strand ends present in unintegrated cDNA promote apoptosis, as is known to be the case for chromosomal double‐strand breaks, and cDNA circularization removes the pro‐apoptotic signal.