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核酸的能力对于所有生命形式中有效的先天免疫系统至关重要，这些核酸丰富且结构相似。事实上，对自身核酸的异常免疫激活可导致有害的自身免疫。在脊椎动物中，细胞用化学方法修饰DNA和RNA核苷，使核酸受体能够区分内源性核酸和入侵病原体的核酸。信使RNA上的腺苷-肌苷（a -to-i）脱氨是由一系列作用于RNA的腺苷脱氨酶（ADAR）催化的。这种修饰作用于抑制细胞质中对宿主源性双链rna的先天免疫反应。最近的研究已经在RNA-DNA杂交体中观察到adar催化的A-to-I修饰，RNA-DNA杂交体是在细胞核转录和DNA复制过程中形成的双链结构。然而，杂交体的A-to-I修饰是否发生在细胞质中尚不清楚，这些核酸物种可以逃逸到细胞质中，从而诱导炎症反应。因此，本项目将结合分子遗传学和生物信息学的方法来研究细胞质杂交中A-to-I的修饰。破译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-理解生命规则-数据驱动的生物学-生物科学的技术发展

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