Abstract
Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutières syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, “second-layer” mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an α-helix bearing an essential catalytic residue.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 164-170 |
| Number of pages | 7 |
| Journal | RNA Biology |
| Volume | 14 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2017 |
Fingerprint
Keywords
- ADAR; Aicardi-Goutieres Syndrome; base-flipping; A to I; inosine; RNA editing
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures. / Fisher, Andrew J; Beal, Peter A.
In: RNA Biology, Vol. 14, No. 2, 01.02.2017, p. 164-170.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Effects of Aicardi-Goutières syndrome mutations predicted from ADAR-RNA structures
AU - Fisher, Andrew J
AU - Beal, Peter A.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutières syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, “second-layer” mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an α-helix bearing an essential catalytic residue.
AB - Adenosine (A) to inosine (I) RNA editing is important for life in metazoan organisms. Dysregulation or mutations that compromise the efficacy of A to I editing results in neurological disorders and a shorten life span. These reactions are catalyzed by adenosine deaminases acting on RNA (ADARs), which hydrolytically deaminate adenosines in regions of duplex RNA. Because inosine mimics guanosine in hydrogen bonding, this prolific RNA editing alters the sequence and structural information in the RNA landscape. Aicardi-Goutières syndrome (AGS) is a severe childhood autoimmune disease that is one of a broader set of inherited disorders characterized by constitutive upregulation of type I interferon (IFN) referred to as type I interferonopathies. AGS is caused by mutations in multiple genes whose protein products, including ADAR1, are all involved in nucleic acid metabolism or sensing. The recent crystal structures of human ADAR2 deaminase domain complexed with duplex RNA substrates enabled modeling of how AGS causing mutations may influence RNA binding and catalysis. The mutations can be broadly characterized into three groups; mutations on RNA-binding loops that directly affect RNA binding, “second-layer” mutations that can alter the disposition of RNA-binding loops, and mutations that can alter the position of an α-helix bearing an essential catalytic residue.
KW - ADAR; Aicardi-Goutieres Syndrome; base-flipping; A to I; inosine; RNA editing
UR - http://www.scopus.com/inward/record.url?scp=85012927694&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85012927694&partnerID=8YFLogxK
U2 - 10.1080/15476286.2016.1267097
DO - 10.1080/15476286.2016.1267097
M3 - Review article
C2 - 27937139
AN - SCOPUS:85012927694
VL - 14
SP - 164
EP - 170
JO - RNA Biology
JF - RNA Biology
SN - 1547-6286
IS - 2
ER -