ADAR1-Mediated RNA Editing and Its Role in Cancer

Abstract

It is well known that the stability of RNA, the interaction between RNA and protein, and the correct translation of protein are significant forces that drive the transition from normal cell to malignant tumor. Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that catalyzes the deamination of adenosine to inosine (A-to-I), which is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. ADAR1-mediated RNA editing is essential for survival in mammals and its dysregulation results in aberrant editing of its substrates that may affect the phenotypic changes in cancer. This overediting phenomenon occurs in many cancers, such as liver, lung, breast, and esophageal cancers, and promotes tumor progression in most cases. In addition to its editing role, ADAR1 can also play an editing-independent role, although current research on this mechanism is relatively shallowly explored in tumors. In this review, we summarize the nature of ADAR1, mechanisms of ADAR1 editing-dependent and editing-independent and implications for tumorigenesis and prognosis, and pay special attention to effects of ADAR1 on cancers by regulating non-coding RNA formation and function.

RNA epigenetic modifications in ovarian cancer: The changes, chances, and challenges

“…A-to-I editing by ADAR1 is generally found in the introns and 3 0 UTRs of coding genes, changing the mRNA stability of cancer-related genes. A small number of A-to-I edited sites are found in the coding region, thus leading to reduced translation of the encoded protein (such as antizyme inhibitor 1 or bladder cancerassociated protein) and affecting cancer progression (Liu et al, 2022). ADAR2 activity is commonly inactivated in cancers (Fritzell et al, 2018).…”

“…ADAR1 and ADAR2 both mediate A‐to‐I editing (Galeano et al, 2012). ADAR1, the most active and powerful deaminase, is upregulated in hepatocellular carcinoma, chronic myeloid leukemia, breast cancer, and other cancers (Barbieri & Kouzarides, 2020; Fritzell et al, 2018; Liu et al, 2022). A‐to‐I editing by ADAR1 is generally found in the introns and 3′UTRs of coding genes, changing the mRNA stability of cancer‐related genes.…”

Structurally Specific Z-DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1

“…13 Given ADAR's multifaceted domain structure, the reported inhibitor only targets the catalytic editing-dependent domain, leaving the other editing-independent functionalities untouched within the cellular milieu that compromises its potential therapeutic capacity. 1 Thus, a relatively more compelling strategy has emerged in the form of targeting ADAR1 for degradation, potentially eradicating the presence of the protein rather than merely inhibiting it. Considering ADAR1's distinctive and inherent affinity for Z-DNA, characterized by its Zig-Zag conformation of the sugar− phosphate backbone under previously elucidated physiological conditions (Figure 1B), 15−17 the incorporation of Z-DNA as a foundational element in the design of PROTAC emerges as the optimal and viable choice.…”

Impact of Disease-Associated Mutations on the Deaminase Activity of ADAR1

“…Proper regulation of ADAR-mediated A to I editing is crucial for maintaining normal cellular function. , Abnormal expression and excessive editing by ADAR1 have been observed in various cancer types, suggesting an involvement in oncogenesis . Interestingly, the knockout of ADAR1 in tumor cells leads to increased sensitivity to immunotherapy, highlighting its potential as a therapeutic target. , ADAR1 also plays a critical role in regulating cytoplasmic innate immunity at the level of double-stranded RNA (dsRNA). , By introduction of structural modifications to RNA, ADAR1-mediated editing prevents the recognition of cellular RNA as foreign, thereby avoiding unnecessary immune responses.…”

“…10,11 Abnormal expression and excessive editing by ADAR1 have been observed in various cancer types, suggesting an involvement in oncogenesis. 12 Interestingly, the knockout of ADAR1 in tumor cells leads to increased sensitivity to immunotherapy, highlighting its potential as a therapeutic target. 13 also plays a critical role in regulating cytoplasmic innate immunity at the level of double-stranded RNA (dsRNA).…”