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Structure and Mechanism of Human DNA Polymerase η
The variant form of human xeroderma pigmentosum syndrome (XPV) is caused by a deficiency in DNA polymerase η (Pol η) that enables replication through sunlight-induced pyrimidine dimers. We report high-resolution crystal structures of human Pol η at four consecutive steps during DNA synthesis through...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899710/ https://www.ncbi.nlm.nih.gov/pubmed/20577208 http://dx.doi.org/10.1038/nature09196 |
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author | Biertümpfel, Christian Zhao, Ye Kondo, Yuji Ramón-Maiques, Santiago Gregory, Mark Lee, Jae Young Masutani, Chikahide Lehmann, Alan R. Hanaoka, Fumio Yang, Wei |
author_facet | Biertümpfel, Christian Zhao, Ye Kondo, Yuji Ramón-Maiques, Santiago Gregory, Mark Lee, Jae Young Masutani, Chikahide Lehmann, Alan R. Hanaoka, Fumio Yang, Wei |
author_sort | Biertümpfel, Christian |
collection | PubMed |
description | The variant form of human xeroderma pigmentosum syndrome (XPV) is caused by a deficiency in DNA polymerase η (Pol η) that enables replication through sunlight-induced pyrimidine dimers. We report high-resolution crystal structures of human Pol η at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol η acts like a molecular splint to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol η orthologs form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. Based on the structures, eight Pol η missense mutations causing XPV can be rationalized as undermining the “molecular splint” or perturbing the active-site alignment. The structures also shed light on the role of Pol η in replicating through D loop and DNA fragile sites. |
format | Text |
id | pubmed-2899710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
record_format | MEDLINE/PubMed |
spelling | pubmed-28997102010-12-01 Structure and Mechanism of Human DNA Polymerase η Biertümpfel, Christian Zhao, Ye Kondo, Yuji Ramón-Maiques, Santiago Gregory, Mark Lee, Jae Young Masutani, Chikahide Lehmann, Alan R. Hanaoka, Fumio Yang, Wei Nature Article The variant form of human xeroderma pigmentosum syndrome (XPV) is caused by a deficiency in DNA polymerase η (Pol η) that enables replication through sunlight-induced pyrimidine dimers. We report high-resolution crystal structures of human Pol η at four consecutive steps during DNA synthesis through cis-syn cyclobutane thymine dimers. Pol η acts like a molecular splint to stabilize damaged DNA in a normal B-form conformation. An enlarged active site accommodates the thymine dimer with excellent stereochemistry for two-metal ion catalysis. Two residues conserved among Pol η orthologs form specific hydrogen bonds with the lesion and the incoming nucleotide to assist translesion synthesis. Based on the structures, eight Pol η missense mutations causing XPV can be rationalized as undermining the “molecular splint” or perturbing the active-site alignment. The structures also shed light on the role of Pol η in replicating through D loop and DNA fragile sites. 2010-06-24 /pmc/articles/PMC2899710/ /pubmed/20577208 http://dx.doi.org/10.1038/nature09196 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Biertümpfel, Christian Zhao, Ye Kondo, Yuji Ramón-Maiques, Santiago Gregory, Mark Lee, Jae Young Masutani, Chikahide Lehmann, Alan R. Hanaoka, Fumio Yang, Wei Structure and Mechanism of Human DNA Polymerase η |
title | Structure and Mechanism of Human DNA Polymerase η |
title_full | Structure and Mechanism of Human DNA Polymerase η |
title_fullStr | Structure and Mechanism of Human DNA Polymerase η |
title_full_unstemmed | Structure and Mechanism of Human DNA Polymerase η |
title_short | Structure and Mechanism of Human DNA Polymerase η |
title_sort | structure and mechanism of human dna polymerase η |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2899710/ https://www.ncbi.nlm.nih.gov/pubmed/20577208 http://dx.doi.org/10.1038/nature09196 |
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