|Title||The RNA editing enzyme APOBEC1 induces somatic mutations and a compatible mutational signature is present in esophageal adenocarcinomas.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Saraconi G, Severi F, Sala C, Mattiuz G, Conticello SG|
|Keywords||Adenocarcinoma, Animals, Benzamides, Cell Line, Chickens, Cytidine Deaminase, Drug Resistance, Neoplasm, Esophageal Neoplasms, Gene Expression Regulation, Humans, Imatinib Mesylate, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutation, Piperazines, Pyrimidines, Rats|
BACKGROUND: The 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.
RESULTS: We 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.
CONCLUSIONS: Our 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.
|Alternate Journal||Genome Biol.|
|PubMed Central ID||PMC4144122|