The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas

Abstract

BackgroundThe AID/APOBECs are deaminases that act on cytosines in a diverse set of pathways and some of them have been linked to the onset of genetic alterations in cancer. Among them, APOBEC1 is the only family member to physiologically target RNA, as the catalytic subunit in the Apolipoprotein B mRNA editing complex. APOBEC1 has been linked to cancer development in mice but its oncogenic mechanisms are not yet well understood.ResultsWe analyze whether expression of APOBEC1 induces a mutator phenotype in vertebrate cells, likely through direct targeting of genomic DNA. We show its ability to increase the inactivation of a stably inserted reporter gene in a chicken cell line that lacks any other AID/APOBEC proteins, and to increase the number of imatinib-resistant clones in a human cellular model for chronic myeloid leukemia through induction of mutations in the BCR-ABL1 fusion gene. Moreover, we find the presence of an AID/APOBEC mutational signature in esophageal adenocarcinomas, a type of tumor where APOBEC1 is expressed, that mimics the one preferred by APOBEC1 in vitro.ConclusionsOur findings suggest that the ability of APOBEC1 to trigger genetic alterations represents a major layer in its oncogenic potential. Such APOBEC1-induced mutator phenotypes could play a role in the onset of esophageal adenocarcinomas. APOBEC1 could be involved in cancer promotion at the very early stages of carcinogenesis, as it is highly expressed in Barrett's esophagus, a condition often associated with esophageal adenocarcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0417-z) contains supplementary material, which is available to authorized users.

Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations

“…Recent publications indicate differing mutational burdens in different cancer types 34, 35. These differences can for example occur as a result of highly mutagenic influences (smoking, sunburn, asbestos, etc), through the inactivation of DNA repair systems or the activation of APOBEC deaminases (apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like) 36. Interestingly, the primary CRC in case number 9 carried a remarkably high number of passenger mutations (see Table 2), possibly caused by an underlying hypermutability deficit.…”

RNA Editors, Cofactors, and mRNA Targets: An Overview of the C-to-U RNA Editing Machinery and Its Implication in Human Disease

“…In primates, Aid and Apobec1 are linked, with the Apobec1 locus being only 1 Mb away from the Aid locus [9]. The main difference between AID and APOBEC1 is the primary physiological choice of the nucleic acid substrate; single stranded DNA for AID, and RNA for APOBEC1 [10,11]. A secondary difference is the presence of a longer coding sequence at the 3′ end of the Apobec1 gene, which might have implications for dimerization [12,13], nucleocytoplasmic transport, and possibly substrate binding [14,15].…”

“…This mutagenic activity is cofactor-independent and significantly higher than AID [10,99]. APOBEC1 DNA editing activity was also shown on herpes and hepatitis viral genomes [100,101] and in mammalian cells [11]. In this context, APOBEC1 somatic mutations have a mutational signature which is present in esophageal adenocarcinomas [11].…”

“…APOBEC1 DNA editing activity was also shown on herpes and hepatitis viral genomes [100,101] and in mammalian cells [11]. In this context, APOBEC1 somatic mutations have a mutational signature which is present in esophageal adenocarcinomas [11]. In addition both AID and APOBEC1 were reported to have 5meC deaminase activity, suggesting a new role as DNA modifiers in cell reprogramming [102].…”

Molecular landscape of esophageal cancer: implications for early detection and personalized therapy

“…While these are likely to be the dominant mutational exposure groups in EAC, a larger scale analysis will be better powered to uncover additional subtypes, and may change the relative prevalence of current signatures. As suggested by other studies, additional signatures related to smoking or to the activity of the cytosine deaminase apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) may prove central to the etiology of EAC (Fig. ).…”