AID/APOBEC cytosine deaminase induces genome-wide kataegis

Abstract

Clusters of localized hypermutation in human breast cancer genomes, named “kataegis” (from the Greek for thunderstorm), are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins. However, a direct link between APOBECs and kataegis is still lacking. We have sequenced the genomes of yeast mutants induced in diploids by expression of the gene for PmCDA1, a hypermutagenic deaminase from sea lamprey. Analysis of the distribution of 5,138 induced mutations revealed localized clusters very similar to those found in tumors. Our data provide evidence that unleashed cytosine deaminase activity is an evolutionary conserved, prominent source of genome-wide kataegis events.ReviewersThis article was reviewed by: Professor Sandor Pongor, Professor Shamil R. Sunyaev, and Dr Vladimir Kuznetsov.

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

“…Other AID/APOBECs have been shown to induce DNA damage and somatic mutations [30,54,55], and they are involved in kataegis, clusters of mutations observed in some cancer genomes [29,32,35,56,57]. An AID/APOBEC mutational signature can be observed in genes highly mutated in cancer [39] and in cancer genomes and exomes [31,[33][34][35]58].…”

A Mathematical Model for Scanning and Catalysis on Single-stranded DNA, Illustrated with Activation-induced Deoxycytidine Deaminase

“…Recent data implicate Apo3B in generating C to T mutations found in breast cancer (44). Expression of AID/Apobec proteins in yeast induces clusters of mutations similar to breast cancer mutation clusters with multiple mutations spaced one to several hundred nucleotides apart on the same DNA strands (45)(46)(47). AID/ Apobec-induced mutation clusters most likely occur by C3 U deaminations on transiently exposed ssDNA formed during double-strand breaks or damaged replication forks (46,47).…”

APOBEC3 genes: retroviral restriction factors to cancer drivers

“…In yeast models A3-induced kataegis was potentiated by, and occurred close to, targeted DSBs introduced using a restriction endonuclease [24]. In the absence of endonuclease-induced DSBs, mutation showers induced by heterologous expression of cytosine deaminases are dependent upon UNG, which is required for the creation of DSBs following removal of uracil from opposing strands (as occurs during AID-induced class-switch recombination; Figure 1), [24,59]. A3-mediated kataegis may therefore be either self-seeding or associated with DSBs arising via other mechanisms.…”