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Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η
Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here tha...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841716/ https://www.ncbi.nlm.nih.gov/pubmed/31704958 http://dx.doi.org/10.1038/s41598-019-52703-7 |
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author | Rechkoblit, Olga Johnson, Robert E. Buku, Angeliki Prakash, Louise Prakash, Satya Aggarwal, Aneel K. |
author_facet | Rechkoblit, Olga Johnson, Robert E. Buku, Angeliki Prakash, Louise Prakash, Satya Aggarwal, Aneel K. |
author_sort | Rechkoblit, Olga |
collection | PubMed |
description | Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here that whereas the high-fidelity replicative polymerase Polδ is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Polη is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Polη with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Polη can accommodate local perturbation caused by the AraC via specific hydrogen bonding and maintain a reaction-ready active site alignment for insertion of both correct and incorrect incoming nucleotides. Taken together, the structures provide a novel basis for the ability of Polη to promote AraC induced mutagenesis in relapsed AML patients. |
format | Online Article Text |
id | pubmed-6841716 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68417162019-11-14 Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η Rechkoblit, Olga Johnson, Robert E. Buku, Angeliki Prakash, Louise Prakash, Satya Aggarwal, Aneel K. Sci Rep Article Cytarabine (AraC) is the mainstay chemotherapy for acute myeloid leukemia (AML). Whereas initial treatment with AraC is usually successful, most AML patients tend to relapse, and AraC treatment-induced mutagenesis may contribute to the development of chemo-resistant leukemic clones. We show here that whereas the high-fidelity replicative polymerase Polδ is blocked in the replication of AraC, the lower-fidelity translesion DNA synthesis (TLS) polymerase Polη is proficient, inserting both correct and incorrect nucleotides opposite a template AraC base. Furthermore, we present high-resolution crystal structures of human Polη with a template AraC residue positioned opposite correct (G) and incorrect (A) incoming deoxynucleotides. We show that Polη can accommodate local perturbation caused by the AraC via specific hydrogen bonding and maintain a reaction-ready active site alignment for insertion of both correct and incorrect incoming nucleotides. Taken together, the structures provide a novel basis for the ability of Polη to promote AraC induced mutagenesis in relapsed AML patients. Nature Publishing Group UK 2019-11-08 /pmc/articles/PMC6841716/ /pubmed/31704958 http://dx.doi.org/10.1038/s41598-019-52703-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rechkoblit, Olga Johnson, Robert E. Buku, Angeliki Prakash, Louise Prakash, Satya Aggarwal, Aneel K. Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η |
title | Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η |
title_full | Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η |
title_fullStr | Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η |
title_full_unstemmed | Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η |
title_short | Structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by DNA polymerase η |
title_sort | structural insights into mutagenicity of anticancer nucleoside analog cytarabine during replication by dna polymerase η |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841716/ https://www.ncbi.nlm.nih.gov/pubmed/31704958 http://dx.doi.org/10.1038/s41598-019-52703-7 |
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