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

Abstract 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.