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DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes
DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-i...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995076/ https://www.ncbi.nlm.nih.gov/pubmed/27455952 http://dx.doi.org/10.1084/jem.20151227 |
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author | Maul, Robert W. MacCarthy, Thomas Frank, Ekaterina G. Donigan, Katherine A. McLenigan, Mary P. Yang, William Saribasak, Huseyin Huston, Donald E. Lange, Sabine S. Woodgate, Roger Gearhart, Patricia J. |
author_facet | Maul, Robert W. MacCarthy, Thomas Frank, Ekaterina G. Donigan, Katherine A. McLenigan, Mary P. Yang, William Saribasak, Huseyin Huston, Donald E. Lange, Sabine S. Woodgate, Roger Gearhart, Patricia J. |
author_sort | Maul, Robert W. |
collection | PubMed |
description | DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-in mice that express full-length Pol ι that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ι did not change overall mutagenesis. We next examined if Pol ι affected tandem mutations generated by another error-prone polymerase, Pol ζ. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol ι–compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol ι occasionally accesses the replication fork to generate a first mutation, and Pol ζ extends the mismatch with a second mutation. |
format | Online Article Text |
id | pubmed-4995076 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-49950762017-02-22 DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes Maul, Robert W. MacCarthy, Thomas Frank, Ekaterina G. Donigan, Katherine A. McLenigan, Mary P. Yang, William Saribasak, Huseyin Huston, Donald E. Lange, Sabine S. Woodgate, Roger Gearhart, Patricia J. J Exp Med Research Articles DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-in mice that express full-length Pol ι that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ι did not change overall mutagenesis. We next examined if Pol ι affected tandem mutations generated by another error-prone polymerase, Pol ζ. The frequency of contiguous mutations was analyzed using a novel computational model to determine if they occur during a single DNA transaction or during two independent events. Analyses of 2,000 mutations from both strains indicated that Pol ι–compromised mice lost the tandem signature, whereas C57BL/6 mice accumulated significant amounts of double mutations. The results support a model where Pol ι occasionally accesses the replication fork to generate a first mutation, and Pol ζ extends the mismatch with a second mutation. The Rockefeller University Press 2016-08-22 /pmc/articles/PMC4995076/ /pubmed/27455952 http://dx.doi.org/10.1084/jem.20151227 Text en @2016 This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Research Articles Maul, Robert W. MacCarthy, Thomas Frank, Ekaterina G. Donigan, Katherine A. McLenigan, Mary P. Yang, William Saribasak, Huseyin Huston, Donald E. Lange, Sabine S. Woodgate, Roger Gearhart, Patricia J. DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
title | DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
title_full | DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
title_fullStr | DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
title_full_unstemmed | DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
title_short | DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
title_sort | dna polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995076/ https://www.ncbi.nlm.nih.gov/pubmed/27455952 http://dx.doi.org/10.1084/jem.20151227 |
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