title: APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts.
abstract: Classic deamination mRNA changes, including cytidine to uridine (C-to-U) and adenosine to inosine (A-to-I), are important exceptions to the central dogma and lead to significant alterations in gene transcripts and products. Although there are a few reports of non-classic mRNA alterations, as yet there is no molecular explanation for these alternative changes. Wilms Tumor 1 (WT1) mutations and variants are implicated in several diseases, including Wilms tumor and acute myeloid leukemia (AML). We observed two alternative G-to-A changes, namely c.1303G>A and c.1586G>A in cDNA clones and found them to be recurrent in a series of 21 umbilical cord blood mononuclear cell (CBMC) samples studied. Two less conserved U-to-C changes were also observed. These alternative changes were found to be significantly higher in non-progenitor as compared to progenitor CBMCs, while they were found to be absent in a series of AML samples studied, indicating they are targeted, cell type-specific mRNA editing modifications. Since APOBEC/ADAR family members are implicated in RNA/DNA editing, we screened them by RNA-interference (RNAi) for WT1-mRNA changes and observed near complete reversal of WT1 c.1303G>A alteration upon APOBEC3A (A3A) knockdown. The role of A3A in mediating this change was confirmed by A3A overexpression in Fujioka cells, which led to a significant increase in WT1 c.1303G>A mRNA editing. Non-progenitor CBMCs showed correspondingly higher levels of A3A-mRNA and protein as compared to the progenitor ones. To our knowledge, this is the first report of mRNA modifying activity for an APOBEC3 protein and implicates A3A in a novel G-to-A form of editing. These findings open the way to further investigations into the mechanisms of other potential mRNA changes, which will help to redefine the RNA editing paradigm in both health and disease.
authors: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom; Digestive Disease Research Institute (DDRI), Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
authors: Ahmadreza
authors: A
authors: Niavarani
authors: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
authors: Erin
authors: E
authors: Currie
authors: Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom.
authors: Yasmin
authors: Y
authors: Reyal
authors: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
authors: Fernando
authors: F
authors: Anjos-Afonso
authors: Department of Bioinformatics, Cancer Research UK, London Research Institute, London, United Kingdom.
authors: Stuart
authors: S
authors: Horswell
authors: INSERM U1065, Mediterranean Centre for Molecular Medicine (C3M), Université Nice Sophia Antipolis, Nice, France.
authors: Emmanuel
authors: E
authors: Griessinger
authors: Instituto de Biología Funcional y Genómica, CSIC/Universidad de Salamanca, Salamanca, Spain.
authors: Jose
authors: J
authors: Luis Sardina
authors: Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, London, United Kingdom.
authors: Dominique
authors: D
authors: Bonnet
mesh_terms: D000241:Adenosine / Q000378:metabolism; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017393:RNA Editing; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014470:Umbilical Cord / Q000166:cytology; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics / Q000473:pathology
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D025721:WT1 Proteins; C583751:WT1 protein, human; D006147:Guanine; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase; D000241:Adenosine