Investigating adenosine-to-inosine modification in RNA-DNA hybrids and the innate immune response

细胞在自身核酸中识别病原体衍生的核酸的能力，其是丰富的且结构相似的，对于所有生命形式中的有效先天免疫系统是至关重要的。事实上，针对自身核酸的异常免疫活化可导致有害的自身免疫。在脊椎动物中，细胞化学修饰DNA和RNA核苷，使得核酸受体可以区分内源性核酸和入侵病原体的核酸。信使RNA上的腺苷至肌苷（A-to-I）脱氨作用由作用于RNA的腺苷脱氨酶（阿达尔）家族催化。这种修饰用于抑制对细胞质中宿主来源的双链RNA的先天免疫应答。最近的研究已经观察到在RNA-DNA杂交体中ADAR催化的A-to-I修饰，RNA-DNA杂交体是在核中转录和DNA复制期间形成的双链结构。然而，尚不清楚杂交体的A至I修饰是否发生在细胞质中，在细胞质中这些核酸物质可以逃逸并因此诱导炎症反应。因此，本项目将结合联合收割机分子遗传学和生物信息学的方法来研究细胞质杂种中的A-to-I修饰。解读碱基修饰对核酸识别的影响是我们理解先天免疫的基础。这对于合成核酸在基因工程和基因治疗中的应用至关重要。UKRI-BBSRC主题和优先事项-了解生命的规则-数据驱动的生物学-生物科学的技术开发

The ability of cells to recognise pathogen-derived nucleic acids amongst self-nucleic acids, which are abundant and structurally similar, is critical for an effective innate immune system in all lifeforms. Indeed, aberrant immune activation towards self-nucleic acids can lead to deleterious autoimmunity. In vertebrates, cells chemically modify DNA and RNA nucleosides so that nucleic acid receptors can distinguish endogenous nucleic acids from those of invading pathogens. Adenosine-to-inosine (A-to-I) deamination on messenger RNA is catalysed by a family of Adenosine Deaminases Acting on RNA (ADAR). This modification acts to suppress innate immune responses to host-derived double-stranded RNAs in the cytoplasm. Recent studies have observed ADAR-catalysed A-to-I modification in RNA-DNA hybrids, which are double-stranded structures that form during transcription and DNA replication in the nucleus. However, it is unknown if A-to-I modification of hybrids occur in the cytoplasm, where these nucleic acid species can escape to and consequently induce inflammatory responses. Therefore, this project will combine molecular genetics and bioinformatic approaches to investigate A-to-I modification in cytoplasmic hybrids. Deciphering the effects of base modifications on nucleic acid recognition is fundamental to our understanding of innate immunity. This is crucial for the application of synthetic nucleic acids in genetic engineering and gene therapies.UKRI-BBSRC Themes and Priorities- Understanding the rules of life- Data-driven biology- Technology development for the biosciences