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. Antiretroviral drugs trigger the increase of LINE-1(L1)-encoded gene products in cancer cells, promoting L1-encoded ORF1p interactions with both DNA repair factors and lamin B1, and ultimately activate retrotransposition-independent autophagy.

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Publication Details

Journal
Communications Biology
Published
2026-09-17
DOI
https://doi.org/10.1038/s42003-026-10900-x
Primary Topic
Autophagy in Disease and Therapy
Type
article
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article

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

Mohammad Salik Zeya Ansari, Ilaria Sciamanna, Roberto Cirilli, Mirko Baranzini et al.
Communications Biology
Autophagy in Disease and Therapy
article

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

Mohammad Salik Zeya Ansari, Ilaria Sciamanna, Roberto Cirilli, Mirko Baranzini, Daniela Trisciuoglio, Patrizia Lavia, Gianluca Sbardella, Anna O'shea, Corrado Spadafora, Leila J Saba, Samira Hozeifi, John LaCava, Paola Rovella, Gerald G. Schumann, Ludovica Altieri, Annalucia Serafino, Michela Damizia, Apostolos Mourtzinos, Federica Andreola, Omar G. Rosas Bringa
article en

Abstract

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. Antiretroviral drugs trigger the increase of LINE-1(L1)-encoded gene products in cancer cells, promoting L1-encoded ORF1p interactions with both DNA repair factors and lamin B1, and ultimately activate retrotransposition-independent autophagy.

Communications Biology
University of Salerno (IT), University Medical Center Groningen (NL), Istituto Superiore di Sanità (IT), Institute of Molecular Biology and Pathology (IT), Istituto di Farmacologia Traslazionale (IT), Rockefeller University (US), Paul Ehrlich Institut (DE)
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Autophagy in Disease and Therapy
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