Figure 7.
Model describing the targeting of TPRT-induced DNA damage with PARPi. An Asxl1/Ezh2 double-mutated (or KO) leukemia cell is depicted (left). Mutation/KO of epigenetic repressors, Asxl1 and Ezh2 (1), leads to chromatin opening; (2) which allows transcription of TEs (3). In the cytoplasm, translation of viral proteins (4) and assembly of RNP complexes (5) take place. Upon re-entry into the nucleus during DNA replication, viral RNA attempts to integrate via TPRT into the host genome (6). Briefly, viral proteins introduce a single-strand break (nick) in the host genome, creating ssDNA, which is protected by PARP proteins. Viral RNA binds to the ssDNA, which serve as a primer for the reverse transcriptase reaction to synthesize viral cDNA, which is then be integrated into the host genome. In the presence of PARPi, PARP proteins–mediated protection of the single-strand breaks/ssDNA is compromised, ultimately leading to excessive DSBs and leukemia cell death (top, right, +PARPi). In the presence of PARPi and RTi, viral RNA integration via TPRT is inhibited (bottom, right, +PARPi and RTi). RTi prevents the synthesis and integration of viral cDNA, thereby minimizing the genomic damage caused by reactivated TEs. As a result, leukemia cell may survive the PARPi treatment. cDNA, complementary DNA; DSB, DNA double-strand break; RNP, ribonucleoprotein.

Model describing the targeting of TPRT-induced DNA damage with PARPi. An Asxl1/Ezh2 double-mutated (or KO) leukemia cell is depicted (left). Mutation/KO of epigenetic repressors, Asxl1 and Ezh2 (1), leads to chromatin opening; (2) which allows transcription of TEs (3). In the cytoplasm, translation of viral proteins (4) and assembly of RNP complexes (5) take place. Upon re-entry into the nucleus during DNA replication, viral RNA attempts to integrate via TPRT into the host genome (6). Briefly, viral proteins introduce a single-strand break (nick) in the host genome, creating ssDNA, which is protected by PARP proteins. Viral RNA binds to the ssDNA, which serve as a primer for the reverse transcriptase reaction to synthesize viral cDNA, which is then be integrated into the host genome. In the presence of PARPi, PARP proteins–mediated protection of the single-strand breaks/ssDNA is compromised, ultimately leading to excessive DSBs and leukemia cell death (top, right, +PARPi). In the presence of PARPi and RTi, viral RNA integration via TPRT is inhibited (bottom, right, +PARPi and RTi). RTi prevents the synthesis and integration of viral cDNA, thereby minimizing the genomic damage caused by reactivated TEs. As a result, leukemia cell may survive the PARPi treatment. cDNA, complementary DNA; DSB, DNA double-strand break; RNP, ribonucleoprotein.

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