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The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis

View Article: PubMed Central - PubMed

ABSTRACT

Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B- breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B- tumours with this mutational bias have at least one copy of A3H-I despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels. Gly105 in A3H-I (versus Arg105 in A3H-II) results in lower protein expression levels and increased nuclear localization, providing a mechanism for accessing genomic DNA. A3H-I also associates with clonal TCA/T-biased mutations in lung adenocarcinoma suggesting this enzyme makes broader contributions to cancer mutagenesis. These studies combine to suggest that A3B and A3H-I, together, explain the bulk of ‘APOBEC signature' mutations in cancer.

No MeSH data available.


Polymorphisms in A3H are not in linkage disequilibrium with A3A or A3B.(a) Heatmap showing the strength of linkage (r2) of SNPs located within the A3H gene versus the rest of the APOBEC3 locus. (b) Bar plots of the A3B deletion and A3H haplotype frequencies for the indicated populations (A3H-I in red; stable A3H-II/V/VII in blue and unstable A3H-III/IV/VI in grey). Superpopulations are colour coded for visualization of larger geographic areas, and individual 3-letter population identifiers are from the 1000 genomes project.
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f2: Polymorphisms in A3H are not in linkage disequilibrium with A3A or A3B.(a) Heatmap showing the strength of linkage (r2) of SNPs located within the A3H gene versus the rest of the APOBEC3 locus. (b) Bar plots of the A3B deletion and A3H haplotype frequencies for the indicated populations (A3H-I in red; stable A3H-II/V/VII in blue and unstable A3H-III/IV/VI in grey). Superpopulations are colour coded for visualization of larger geographic areas, and individual 3-letter population identifiers are from the 1000 genomes project.

Mentions: Interestingly, we found that the A3H gene is only linked strongly to itself and to the immediate upstream gene, A3G. Linkage is weaker with genes further upstream, A3D and A3F, and completely absent with A3A, A3B and A3C (Fig. 2a). Although A3G is linked to A3H, it is very unlikely to be involved in cancer mutagenesis because the encoded enzyme has an intrinsic preference for the 3′ cytosine in CC and CCC motifs5354, which are rarely mutated in cancer (for example, Fig. 1 for cytosine mutations in breast cancer). Importantly, this linkage analysis shows that the A3H gene is unlinked to A3A (or the A3A-B chimeric gene resulting from the A3B deletion), suggesting that the significant association with A3H-I and APOBEC signature mutations in A3B- tumours may be due directly to A3H-I enzymatic activity and not to A3A (as favoured by recent studies7161718192021) nor to any other TC-preferring enzyme encoded by the locus.


The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis
Polymorphisms in A3H are not in linkage disequilibrium with A3A or A3B.(a) Heatmap showing the strength of linkage (r2) of SNPs located within the A3H gene versus the rest of the APOBEC3 locus. (b) Bar plots of the A3B deletion and A3H haplotype frequencies for the indicated populations (A3H-I in red; stable A3H-II/V/VII in blue and unstable A3H-III/IV/VI in grey). Superpopulations are colour coded for visualization of larger geographic areas, and individual 3-letter population identifiers are from the 1000 genomes project.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036005&req=5

f2: Polymorphisms in A3H are not in linkage disequilibrium with A3A or A3B.(a) Heatmap showing the strength of linkage (r2) of SNPs located within the A3H gene versus the rest of the APOBEC3 locus. (b) Bar plots of the A3B deletion and A3H haplotype frequencies for the indicated populations (A3H-I in red; stable A3H-II/V/VII in blue and unstable A3H-III/IV/VI in grey). Superpopulations are colour coded for visualization of larger geographic areas, and individual 3-letter population identifiers are from the 1000 genomes project.
Mentions: Interestingly, we found that the A3H gene is only linked strongly to itself and to the immediate upstream gene, A3G. Linkage is weaker with genes further upstream, A3D and A3F, and completely absent with A3A, A3B and A3C (Fig. 2a). Although A3G is linked to A3H, it is very unlikely to be involved in cancer mutagenesis because the encoded enzyme has an intrinsic preference for the 3′ cytosine in CC and CCC motifs5354, which are rarely mutated in cancer (for example, Fig. 1 for cytosine mutations in breast cancer). Importantly, this linkage analysis shows that the A3H gene is unlinked to A3A (or the A3A-B chimeric gene resulting from the A3B deletion), suggesting that the significant association with A3H-I and APOBEC signature mutations in A3B- tumours may be due directly to A3H-I enzymatic activity and not to A3A (as favoured by recent studies7161718192021) nor to any other TC-preferring enzyme encoded by the locus.

View Article: PubMed Central - PubMed

ABSTRACT

Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B- breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B- tumours with this mutational bias have at least one copy of A3H-I despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels. Gly105 in A3H-I (versus Arg105 in A3H-II) results in lower protein expression levels and increased nuclear localization, providing a mechanism for accessing genomic DNA. A3H-I also associates with clonal TCA/T-biased mutations in lung adenocarcinoma suggesting this enzyme makes broader contributions to cancer mutagenesis. These studies combine to suggest that A3B and A3H-I, together, explain the bulk of ‘APOBEC signature' mutations in cancer.

No MeSH data available.