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.
Highlights
Clusters of localized hypermutation in human breast cancer genomes, named “kataegis”, are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins
Based on the prevalence of C:G->T:A transitions in these regions and the sequence context of the mutations, it has been hypothesized that mutation clusters in cancer are induced by AID/APOBEC editing deaminases [2,3]
This is consistent with the ability of deaminases to produce multiple deaminations in Single-stranded DNA (ssDNA) in vitro that can be recovered as clustered mutations in bacteria [4,5]
Summary
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. Based on the prevalence of C:G->T:A transitions in these regions and the sequence context of the mutations, it has been hypothesized that mutation clusters in cancer are induced by AID/APOBEC editing deaminases [2,3]. We sequenced this hypermutable region in Canr mutants induced by a different deaminase, human AID, and found mutations in 2 out of 12 clones (Figure 1D).
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