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Low-fidelity DNA synthesis by human DNA polymerase theta

Human DNA polymerase theta (pol θ or POLQ) is a proofreading-deficient family A enzyme implicated in translesion synthesis (TLS) and perhaps in somatic hypermutation (SHM) of immunoglobulin genes. These proposed functions and kinetic studies imply that pol θ may synthesize DNA with low fidelity. Her...

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Autores principales: Arana, Mercedes E., Seki, Mineaki, Wood, Richard D., Rogozin, Igor B., Kunkel, Thomas A.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441791/
https://www.ncbi.nlm.nih.gov/pubmed/18503084
http://dx.doi.org/10.1093/nar/gkn310
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author Arana, Mercedes E.
Seki, Mineaki
Wood, Richard D.
Rogozin, Igor B.
Kunkel, Thomas A.
author_facet Arana, Mercedes E.
Seki, Mineaki
Wood, Richard D.
Rogozin, Igor B.
Kunkel, Thomas A.
author_sort Arana, Mercedes E.
collection PubMed
description Human DNA polymerase theta (pol θ or POLQ) is a proofreading-deficient family A enzyme implicated in translesion synthesis (TLS) and perhaps in somatic hypermutation (SHM) of immunoglobulin genes. These proposed functions and kinetic studies imply that pol θ may synthesize DNA with low fidelity. Here, we show that when copying undamaged DNA, pol θ generates single base errors at rates 10- to more than 100-fold higher than for other family A members. Pol θ adds single nucleotides to homopolymeric runs at particularly high rates, exceeding 1% in certain sequence contexts, and generates single base substitutions at an average rate of 2.4 × 10(−3), comparable to inaccurate family Y human pol κ (5.8 × 10(−3)) also implicated in TLS. Like pol κ, pol θ is processive, implying that it may be tightly regulated to avoid deleterious mutagenesis. Pol θ also generates certain base substitutions at high rates within sequence contexts similar to those inferred to be copied by pol θ during SHM of immunoglobulin genes in mice. Thus, pol θ is an exception among family A polymerases, and its low fidelity is consistent with its proposed roles in TLS and SHM.
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spelling pubmed-24417912008-07-02 Low-fidelity DNA synthesis by human DNA polymerase theta Arana, Mercedes E. Seki, Mineaki Wood, Richard D. Rogozin, Igor B. Kunkel, Thomas A. Nucleic Acids Res Nucleic Acid Enzymes Human DNA polymerase theta (pol θ or POLQ) is a proofreading-deficient family A enzyme implicated in translesion synthesis (TLS) and perhaps in somatic hypermutation (SHM) of immunoglobulin genes. These proposed functions and kinetic studies imply that pol θ may synthesize DNA with low fidelity. Here, we show that when copying undamaged DNA, pol θ generates single base errors at rates 10- to more than 100-fold higher than for other family A members. Pol θ adds single nucleotides to homopolymeric runs at particularly high rates, exceeding 1% in certain sequence contexts, and generates single base substitutions at an average rate of 2.4 × 10(−3), comparable to inaccurate family Y human pol κ (5.8 × 10(−3)) also implicated in TLS. Like pol κ, pol θ is processive, implying that it may be tightly regulated to avoid deleterious mutagenesis. Pol θ also generates certain base substitutions at high rates within sequence contexts similar to those inferred to be copied by pol θ during SHM of immunoglobulin genes in mice. Thus, pol θ is an exception among family A polymerases, and its low fidelity is consistent with its proposed roles in TLS and SHM. Oxford University Press 2008-06 2008-05-24 /pmc/articles/PMC2441791/ /pubmed/18503084 http://dx.doi.org/10.1093/nar/gkn310 Text en © 2008 The Author(s) http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Nucleic Acid Enzymes
Arana, Mercedes E.
Seki, Mineaki
Wood, Richard D.
Rogozin, Igor B.
Kunkel, Thomas A.
Low-fidelity DNA synthesis by human DNA polymerase theta
title Low-fidelity DNA synthesis by human DNA polymerase theta
title_full Low-fidelity DNA synthesis by human DNA polymerase theta
title_fullStr Low-fidelity DNA synthesis by human DNA polymerase theta
title_full_unstemmed Low-fidelity DNA synthesis by human DNA polymerase theta
title_short Low-fidelity DNA synthesis by human DNA polymerase theta
title_sort low-fidelity dna synthesis by human dna polymerase theta
topic Nucleic Acid Enzymes
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441791/
https://www.ncbi.nlm.nih.gov/pubmed/18503084
http://dx.doi.org/10.1093/nar/gkn310
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