Reverse transcriptase inhibitors induce autophagy in a LINE-1 ORF1p-dependent manner

Human Long INterspersed Element-1 (LINE-1) retrotransposons propagate throughout the genome via reverse-transcribed RNA intermediates. Their expression is pervasive in cancer. Full-length LINE-1s encode two proteins: ORF1p, an RNA-binding protein, and ORF2p, harboring reverse transcriptase (RT) and endonuclease activities. Non-nucleoside RT inhibitors (NNRTI) and nucleoside RT inhibitors (NRTI) down-regulate cancer cell proliferation and antagonize cancer progression. We previously reported that two NNRTIs induced DNA damage, nuclear lamin ruptures, micronuclei formation, and up-regulated autophagy markers, in prostate cancer cells. Here we show that both the NNRTI SPV122.2 and the NRTI Abacavir up-regulate LINE-1 mRNA and ORF1p abundance in nuclei, triggering novel ORF1p interactions with lamin B1 and with DNA damage factors. ORF1p accumulates with damaged DNA and with the autophagy receptor p62 within micronuclei. Inhibiting autophagy, or decreasing ORF1p levels, prevent DNA damage and preserve lamin B1 integrity, uncovering roles of LINE-1 and ORF1p in autophagy that are independent of retrotranscription events.