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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...

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Autores principales: Biertümpfel, Christian, Zhao, Ye, Kondo, Yuji, Ramón-Maiques, Santiago, Gregory, Mark, Lee, Jae Young, Masutani, Chikahide, Lehmann, Alan R., Hanaoka, Fumio, Yang, Wei
Formato: Texto
Lenguaje:English
Publicado: 2010
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.
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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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