A Unique Chimeric RNA: ERCC1‐iASPP Drives Benzo[a]pyrene‐Induced Lung Carcinogenesis via Dual Coding and Non‐Coding Mechanisms

Genetic variation at 19q13.3 critically modulates chemical carcinogen-induced lung carcinogenesis, particularly in mediating the activity of benzo[a]pyrene (B[a]P), a major polycyclic aromatic hydrocarbon (PAH) carcinogen. The adjacent genes ERCC1 and iASPP within this locus respectively coordinate nucleotide excision repair of PAH-induced DNA damage and suppression of apoptotic pathways. Their synergistic interaction regulates pivotal molecular events during PAH-driven lung carcinogenesis, ultimately impacting cellular repair, proliferation, and apoptosis. Chimeric RNAs have been increasingly recognized as promising biomarkers and therapeutic targets in cancer. However, the characterization of lung cancer-specific chimeric RNAs in the context of chemical carcinogenesis remains limited. This study identifies and characterizes ERCC1-iASPP, a novel chimeric RNA derived from the neighboring genes ERCC1 and iASPP, which exerts tumor-promoting functions via coding and non-coding mechanisms. First, the chimeric transcript encodes a previously uncharacterized protein, Ei, which enhances USP45-mediated deubiquitination of ERCC1, thereby stabilizing ERCC1 protein. Additionally, ERCC1-iASPP also functions as a (long non-coding chimeric RNA, lnccRNA): in the cytoplasm, it acts as a (competing endogenous RNA, ceRNA) by sequestering miR-143-3p, leading to derepression of CDK1 and PGK1 and subsequent activation of oncogenic pathways, while in the nucleus, ERCC1-iASPP further promotes transcriptional activation by recruiting STAT4 to the PGK1 promoter. Collectively, these findings establish ERCC1-iASPP as a bifunctional RNA with both protein-coding and non-coding regulatory roles that cooperatively promote B[a]P-induced lung tumorigenesis. This study highlights ERCC1-iASPP as a potential diagnostic and therapeutic target in smoking-related lung cancer.