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The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis
Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B-null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B-null tumours with...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036005/ https://www.ncbi.nlm.nih.gov/pubmed/27650891 http://dx.doi.org/10.1038/ncomms12918 |
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author | Starrett, Gabriel J. Luengas, Elizabeth M. McCann, Jennifer L. Ebrahimi, Diako Temiz, Nuri A. Love, Robin P. Feng, Yuqing Adolph, Madison B. Chelico, Linda Law, Emily K. Carpenter, Michael A. Harris, Reuben S |
author_facet | Starrett, Gabriel J. Luengas, Elizabeth M. McCann, Jennifer L. Ebrahimi, Diako Temiz, Nuri A. Love, Robin P. Feng, Yuqing Adolph, Madison B. Chelico, Linda Law, Emily K. Carpenter, Michael A. Harris, Reuben S |
author_sort | Starrett, Gabriel J. |
collection | PubMed |
description | Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B-null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B-null 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. |
format | Online Article Text |
id | pubmed-5036005 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50360052016-10-04 The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis Starrett, Gabriel J. Luengas, Elizabeth M. McCann, Jennifer L. Ebrahimi, Diako Temiz, Nuri A. Love, Robin P. Feng, Yuqing Adolph, Madison B. Chelico, Linda Law, Emily K. Carpenter, Michael A. Harris, Reuben S Nat Commun Article Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B-null breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B-null 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. Nature Publishing Group 2016-09-21 /pmc/articles/PMC5036005/ /pubmed/27650891 http://dx.doi.org/10.1038/ncomms12918 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Starrett, Gabriel J. Luengas, Elizabeth M. McCann, Jennifer L. Ebrahimi, Diako Temiz, Nuri A. Love, Robin P. Feng, Yuqing Adolph, Madison B. Chelico, Linda Law, Emily K. Carpenter, Michael A. Harris, Reuben S The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis |
title | The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis |
title_full | The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis |
title_fullStr | The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis |
title_full_unstemmed | The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis |
title_short | The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis |
title_sort | dna cytosine deaminase apobec3h haplotype i likely contributes to breast and lung cancer mutagenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036005/ https://www.ncbi.nlm.nih.gov/pubmed/27650891 http://dx.doi.org/10.1038/ncomms12918 |
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