Aryl hydrocarbon receptor is involved in DNA damage repair after liver injury with diethylnitrosamine in mice

Abstract Aryl hydrocarbon receptor (AhR) is a transcription factor traditionally involved in toxicological and carcinogenic cellular processes linked to xenobiotics. In recent decades, a new physiological role has emerged, in which AhR has been shown to be a key regulator of different processes such as the cell cycle, cell proliferation, apoptosis, pluripotency, and stemness. Recent studies have suggested a possible role for AhR in the DNA damage response (DDR) and repair mechanisms. To assess this point, in this work we used diethylnitrosamine (DEN) to induce liver injury and DNA damage in wild type (WT) and AhR knockout (KO) mice. We analysed the protein expression levels of several DDR (H2AX, 53BP1, and BRCA1) and cell proliferation (Ki67, AFP, and PCNA) markers. Therefore, we demonstrate that following DNA damage, the absence of AhR results in a shift towards apoptosis and compensatory proliferation mechanisms, accompanied by reduced repair fidelity of DNA damage compared with than in WT mice, compromising genomic stability. We also mapped the interactome profile of AhR, identifying new partners involved in both repair and proliferation processes. In conclusion, our results highlight the relevant role of AhR in cell proliferation and DNA repair processes, which can be key in different pathologies, such as cancer.