Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey
from Weird to Wondrous

KEEGAN, Liam, Khadija HAJJI and Mary Anne O'CONNELL. Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous. Accounts of chemical research. WASHINGTON: American Chemical Society, 2023, vol. 56, No 22, p. 3165-3174. ISSN 0001-4842. Available from: https://dx.doi.org/10.1021/acs.accounts.3c00433.

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TY  - JOUR
ID  - 2380617
AU  - Keegan, Liam - Hajji, Khadija - O'Connell, Mary Anne
PY  - 2023
TI  - Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous
JF  - Accounts of chemical research
VL  - 56
IS  - 22
SP  - 3165-3174
EP  - 3165-3174
PB  - American Chemical Society
SN  - 00014842
KW  - EDITING ENZYME;MESSENGER-RNAS
KW  - DROSOPHILA
KW  - PURIFICATION
KW  - INOSINE
KW  - MUTATION
KW  - SDSRNA
UR  - https://pubs.acs.org/doi/10.1021/acs.accounts.3c00433
N2  - The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are essential for many biological functions including nervous system function, hematopoiesis, and innate immunity. Initially it was assumed that the wide-ranging biological roles of ADARs are due to inosine in mRNA being read as guanosine by the translational machinery, allowing incomplete RNA editing in a target codon to generate two different proteins from the same primary transcript. In humans, there are approximately seventy-six positions that undergo site-specific editing in tissues at greater than 20% efficiency that result in recoding. Many of these transcripts are expressed in the central nervous system (CNS) and edited by ADAR2. Exploiting mouse genetic models revealed that transgenic mice lacking the gene encoding Adar2 die within 3 weeks of birth. Therefore, the role of ADAR2 in generating protein diversity in the nervous system is clear, but why is ADAR RNA editing activity essential in other biological processes, particularly editing mainly involving ADAR1? ADAR1 edits human transcripts having embedded Alu element inverted repeats (AluIRs), but the link from this activity to innate immunity activation was elusive. Mice lacking the gene encoding Adar1 are embryonically lethal, and a major breakthrough was the discovery that the role of Adar1 in innate immunity is due to its ability to edit such repetitive element inverted repeats which have the ability to form dsRNA in transcripts. The presence of inosine prevents activation of the dsRNA sensor melanoma differentiation-associated protein 5 (Mda5). Thus, inosine helps the cell discriminate self from non-self RNA, acting like a barcode on mRNA. As innate immunity is key to many different biological processes, the basis for this widespread biological role of the ADAR1 enzyme became evident.Our group has been studying ADARs from the outset of research on these enzymes. In this Account, we give a historical perspective, moving from the initial purification of ADAR1 and ADAR2 and cloning of their encoding genes up to the current research focus in the field and what questions still remain to be addressed. We discuss the characterizations of the proteins, their localizations, posttranslational modifications, and dimerization, and how all of these affect their biological activities. Another aspect we explore is the use of mouse and Drosophila genetic models to study ADAR functions and how these were crucial in determining the biological functions of the ADAR proteins. Finally, we describe the severe consequences of rare mutations found in the human genes encoding ADAR1 and ADAR2.
ER  -

Basic information
Original name	Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous
Authors	KEEGAN, Liam (372 Ireland, belonging to the institution), Khadija HAJJI (788 Tunisia, belonging to the institution) and Mary Anne O'CONNELL (372 Ireland, guarantor, belonging to the institution).
Edition	Accounts of chemical research, WASHINGTON, American Chemical Society, 2023, 0001-4842.

Other information
Original language	English
Type of outcome	Article in a journal
Field of Study	10400 1.4 Chemical sciences
Country of publisher	United States of America
Confidentiality degree	is not subject to a state or trade secret
WWW	URL
Impact factor	Impact factor: 18.300 in 2022
RIV identification code	RIV/00216224:14740/23:00134417
Organization unit	Central European Institute of Technology
Doi	http://dx.doi.org/10.1021/acs.accounts.3c00433
UT WoS	001096861500001
Keywords in English	EDITING ENZYME;MESSENGER-RNAS; DROSOPHILA; PURIFICATION; INOSINE; MUTATION; SDSRNA
Tags	rivok
Tags	International impact, Reviewed
Changed by	Changed by: Mgr. Eva Dubská, učo 77638. Changed: 3/3/2024 17:30.

Abstract

The adenosine deaminase acting on RNA (ADAR) enzymes that catalyze the conversion of adenosine to inosine in double-stranded (ds)RNA are evolutionarily conserved and are essential for many biological functions including nervous system function, hematopoiesis, and innate immunity. Initially it was assumed that the wide-ranging biological roles of ADARs are due to inosine in mRNA being read as guanosine by the translational machinery, allowing incomplete RNA editing in a target codon to generate two different proteins from the same primary transcript. In humans, there are approximately seventy-six positions that undergo site-specific editing in tissues at greater than 20% efficiency that result in recoding. Many of these transcripts are expressed in the central nervous system (CNS) and edited by ADAR2. Exploiting mouse genetic models revealed that transgenic mice lacking the gene encoding Adar2 die within 3 weeks of birth. Therefore, the role of ADAR2 in generating protein diversity in the nervous system is clear, but why is ADAR RNA editing activity essential in other biological processes, particularly editing mainly involving ADAR1? ADAR1 edits human transcripts having embedded Alu element inverted repeats (AluIRs), but the link from this activity to innate immunity activation was elusive. Mice lacking the gene encoding Adar1 are embryonically lethal, and a major breakthrough was the discovery that the role of Adar1 in innate immunity is due to its ability to edit such repetitive element inverted repeats which have the ability to form dsRNA in transcripts. The presence of inosine prevents activation of the dsRNA sensor melanoma differentiation-associated protein 5 (Mda5). Thus, inosine helps the cell discriminate self from non-self RNA, acting like a barcode on mRNA. As innate immunity is key to many different biological processes, the basis for this widespread biological role of the ADAR1 enzyme became evident.Our group has been studying ADARs from the outset of research on these enzymes. In this Account, we give a historical perspective, moving from the initial purification of ADAR1 and ADAR2 and cloning of their encoding genes up to the current research focus in the field and what questions still remain to be addressed. We discuss the characterizations of the proteins, their localizations, posttranslational modifications, and dimerization, and how all of these affect their biological activities. Another aspect we explore is the use of mouse and Drosophila genetic models to study ADAR functions and how these were crucial in determining the biological functions of the ADAR proteins. Finally, we describe the severe consequences of rare mutations found in the human genes encoding ADAR1 and ADAR2.

Links
GX21-27329X, research and development project	Name: ADAR-dependentní RNA editace; Jak imunitní systém a mozek porušují Centrální Dogma.
GX21-27329X, research and development project	Investor: Czech Science Foundation

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Adenosine Deaminase Acting on RNA (ADAR) Enzymes: A Journey from Weird to Wondrous

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