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

## TL;DR

A new chimeric RNA called ERCC1-iASPP helps drive lung cancer caused by a chemical carcinogen through both coding and non-coding mechanisms.

## Contribution

ERCC1-iASPP is a novel bifunctional RNA that promotes lung carcinogenesis via dual regulatory and protein-coding roles.

## Key findings

- ERCC1-iASPP encodes a protein Ei that stabilizes ERCC1 via USP45-mediated deubiquitination.
- ERCC1-iASPP acts as a ceRNA in the cytoplasm, derepressing CDK1 and PGK1 via miR-143-3p sequestration.
- In the nucleus, ERCC1-iASPP recruits STAT4 to the PGK1 promoter, promoting transcriptional activation.

## 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.

The chimeric RNA ERCC1‐iASPP possesses dual coding and non‐coding functions, synergistically accelerating the process of cellular malignant transformation.