Fig. 8: ME-derived DNA adducts, transcription stress and activation of canonical TC-NER to prevent genomic instability and cell death. | Cell Death & Disease

Fig. 8: ME-derived DNA adducts, transcription stress and activation of canonical TC-NER to prevent genomic instability and cell death.

From: Transcription-coupled nucleotide excision repair protects against genomic instability and cell death induced by the liver toxin methyleugenol

Fig. 8: ME-derived DNA adducts, transcription stress and activation of canonical TC-NER to prevent genomic instability and cell death.The alternative text for this image may have been generated using AI.

OH-ME as main phase I metabolite of ME causes DNA adducts (N2-MIE-dG » N6-MIE-dA) upon metabolic activation by SULT enzymes. ME-derived DNA adducts are not subjected to GG-NER, but persist in the global genome. Adducts in the transcribed region of the genome stall RNA polymerase II (RNAPII), which results in immobilization of CSB followed by the recruitment of CSA and UVSSA. CSA promotes the ubiquitination and proteasomal degradation of CSB upon OH-ME treatment, whereas UVSSA counteracts this process via USP7. The RPB1 subunit of stalled RNAPII is released from chromatin and exported into the cytoplasm for proteasomal degradation. At low DNA adduct levels, the triggered canonical TC-NER pathway removes the lesions, preserves genome integrity and promotes cell survival. At high DNA adduct levels, persistent transcription stress provokes genomic instability (formation of R-loops and micronuclei) and induces apoptotic cell death. Cells deficient in TC-NER (CSA–/– or CSB–/–) or in both NER subpathways (XPA–/–) are hypersensitive to ME-derived DNA adducts, resulting in a hyperactivated DNA damage response (DDR), increased cell death induction and genomic instability. Created in BioRender. Fahrer, J. (2026) https://BioRender.com/c09atmy.

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