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<p>Under stress conditions, endogenous biomolecules such as nucleic acids or proteins can be released from damaged cells and considered as damage-associated molecular patterns (DAMPs) activating innate immune system and context-dependent responses. In the present study, self-extracellular RNA was obtained from dying (RNA D) and senescent (RNA S) cellular models of osteosarcoma (OS), characterized by NGS, and tested against proliferating and non-proliferating (etoposide-indued senescent) OS cells (U-2 OS, SaOS-2, MG-63, 143B). RNA D and RNA S induced apoptosis, nitro-oxidative stress, nucleic acid sensing pathways and cytokine production, and RNA m<sup>5</sup>C methyltransferase-based responses (TRDMT1 and NSUN2) in proliferating OS cells. In drug-induced senescent OS cells, <i>TRDMT1</i> gene knockout (KO) prevented STING activation, related proinflammatory response, and cell death. Furthermore, IFN-β binding RNA partners were identified, namely <i>NSUN2</i>, <i>NSUN5</i>, <i>NSUN6</i>, <i>CDKN1A</i>, <i>MYC</i>, and <i>RAD51</i> transcripts and these interactions were compromised in <i>TRDMT1</i> KO cells and upon RNA D and RNA S treatment. <i>TRDMT1</i> KO also resulted in replication stress in OS cells that was potentiated by RNA D and RNA S stimulation and associated with elevated levels of APOBEC3A and APOBEC3G, members of the cytidine deaminase protein family. In conclusion, we showed that <i>TRDMT1</i> KO restricted STING-based immune and cell death response to RNA D and RNA S in non-proliferating drug resistant OS cells that might have potential therapeutic implications.</p>

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TRDMT1 methyltransferase gene knockout attenuates STING-based cell death signaling during self-extracellular RNA-mediated response in drug-induced senescent osteosarcoma cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月13日

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  • Gabriela Betlej,
  • Anna Deręgowska,
  • Maciej Wnuk,
  • Dominika Błoniarz,
  • Tomasz Szmatoła,
  • Katarzyna Klimczak,
  • Jagoda Adamczyk-Grochala,
  • Julia Świętoń,
  • Anna Lewińska

摘要

Under stress conditions, endogenous biomolecules such as nucleic acids or proteins can be released from damaged cells and considered as damage-associated molecular patterns (DAMPs) activating innate immune system and context-dependent responses. In the present study, self-extracellular RNA was obtained from dying (RNA D) and senescent (RNA S) cellular models of osteosarcoma (OS), characterized by NGS, and tested against proliferating and non-proliferating (etoposide-indued senescent) OS cells (U-2 OS, SaOS-2, MG-63, 143B). RNA D and RNA S induced apoptosis, nitro-oxidative stress, nucleic acid sensing pathways and cytokine production, and RNA m5C methyltransferase-based responses (TRDMT1 and NSUN2) in proliferating OS cells. In drug-induced senescent OS cells, TRDMT1 gene knockout (KO) prevented STING activation, related proinflammatory response, and cell death. Furthermore, IFN-β binding RNA partners were identified, namely NSUN2, NSUN5, NSUN6, CDKN1A, MYC, and RAD51 transcripts and these interactions were compromised in TRDMT1 KO cells and upon RNA D and RNA S treatment. TRDMT1 KO also resulted in replication stress in OS cells that was potentiated by RNA D and RNA S stimulation and associated with elevated levels of APOBEC3A and APOBEC3G, members of the cytidine deaminase protein family. In conclusion, we showed that TRDMT1 KO restricted STING-based immune and cell death response to RNA D and RNA S in non-proliferating drug resistant OS cells that might have potential therapeutic implications.