ADAR-Mediated A>I(G) RNA Editing in the Genotoxic Drug Response of Breast Cancer

Abstract

Epitranscriptomics is a field that delves into post-transcriptional changes. Among these modifications, the conversion of adenosine to inosine, traduced as guanosine (A>I(G)), is one of the known RNA-editing mechanisms, catalyzed by ADARs. This type of RNA editing is the most common type of editing in mammals and contributes to biological diversity. Disruption in the A>I(G) RNA-editing balance has been linked to diseases, including several types of cancer. Drug resistance in patients with cancer represents a significant public health concern, contributing to increased mortality rates resulting from therapy non-responsiveness and disease progression, representing the greatest challenge for researchers in this field. The A>I(G) RNA editing is involved in several mechanisms over the immunotherapy and genotoxic drug response and drug resistance. This review investigates the relationship between ADAR1 and specific A>I(G) RNA-edited sites, focusing particularly on breast cancer, and the impact of these sites on DNA damage repair and the immune response over anti-cancer therapy. We address the underlying mechanisms, bioinformatics, and in vitro strategies for the identification and validation of A>I(G) RNA-edited sites. We gathered databases related to A>I(G) RNA editing and cancer and discussed the potential clinical and research implications of understanding A>I(G) RNA-editing patterns. Understanding the intricate role of ADAR1-mediated A>I(G) RNA editing in breast cancer holds significant promise for the development of personalized treatment approaches tailored to individual patients' A>I(G) RNA-editing profiles.

Keywords: A>I(G); ADAR1; DNA damage repair; RNA editing; breast cancer; drug resistance; drug response; immune response; splicing alteration.

Figure 1

Scheme of ADAR1-mediated A>I(G) RNA editing. (A) ADAR1 activity function in DNA damage repair machinery such as ATM, ATR, GINS4, POLH, ZEB1, and CtIP from double-strand DNA breaks (DSB); (B) effect of ADAR1-mediated A>I(G) RNA-edited dsRNA and non-edited dsRNA on MDA5/MAVS/PKR function and I Interferon-Stimulated Genes (ISGs). Adapted from Nakahama T. and Kawahara Y. [30].

Figure 2

Impact of ADAR1 expression on immunotherapy response. (A) High ADAR1 expression reduces immunogenicity and increases neoantigen production, leading to decreased susceptibility to apoptosis and a reduced response to immune checkpoint inhibitors (ICIs). (B) Low ADAR1 expression enhances immunogenicity and increases susceptibility to apoptosis, resulting in an improved response to ICIs. Adapted from Nakahama T. and Kawahara Y. [30].

Figure 3

Flowchart illustrating the ADAR1-mediated RNA-editing application from the molecular consequences to clinical applications as prognosis and predictive biomarkers in BC.