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Structural insights into DNA degradation by human mitochondrial nuclease MGME1

Mitochondrial nucleases play important roles in accurate maintenance and correct metabolism of mtDNA, the own genetic materials of mitochondria that are passed exclusively from mother to child. MGME1 is a highly conserved DNase that was discovered recently. Mutations in MGME1-coding gene lead to sev...

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Autores principales: Yang, Chun, Wu, Ruiqi, Liu, Hehua, Chen, Yiqing, Gao, Yanqing, Chen, Xi, Li, Yangyang, Ma, Jinbiao, Li, Jixi, Gan, Jianhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237815/
https://www.ncbi.nlm.nih.gov/pubmed/30247721
http://dx.doi.org/10.1093/nar/gky855
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author Yang, Chun
Wu, Ruiqi
Liu, Hehua
Chen, Yiqing
Gao, Yanqing
Chen, Xi
Li, Yangyang
Ma, Jinbiao
Li, Jixi
Gan, Jianhua
author_facet Yang, Chun
Wu, Ruiqi
Liu, Hehua
Chen, Yiqing
Gao, Yanqing
Chen, Xi
Li, Yangyang
Ma, Jinbiao
Li, Jixi
Gan, Jianhua
author_sort Yang, Chun
collection PubMed
description Mitochondrial nucleases play important roles in accurate maintenance and correct metabolism of mtDNA, the own genetic materials of mitochondria that are passed exclusively from mother to child. MGME1 is a highly conserved DNase that was discovered recently. Mutations in MGME1-coding gene lead to severe mitochondrial syndromes characterized by external ophthalmoplegia, emaciation, and respiratory failure in humans. Unlike many other nucleases that are distributed in multiple cellular organelles, human MGME1 is a mitochondria-specific nuclease; therefore, it can serve as an ideal target for treating related syndromes. Here, we report one HsMGME1-Mn(2+) complex and three different HsMGME1-DNA complex structures. In combination with in vitro cleavage assays, our structures reveal the detailed molecular basis for substrate DNA binding and/or unwinding by HsMGME1. Besides the conserved two-cation-assisted catalytic mechanism, structural analysis of HsMGME1 and comparison with homologous proteins also clarified substrate binding and cleavage directionalities of the DNA double-strand break repair complexes RecBCD and AddAB.
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spelling pubmed-62378152018-11-21 Structural insights into DNA degradation by human mitochondrial nuclease MGME1 Yang, Chun Wu, Ruiqi Liu, Hehua Chen, Yiqing Gao, Yanqing Chen, Xi Li, Yangyang Ma, Jinbiao Li, Jixi Gan, Jianhua Nucleic Acids Res Structural Biology Mitochondrial nucleases play important roles in accurate maintenance and correct metabolism of mtDNA, the own genetic materials of mitochondria that are passed exclusively from mother to child. MGME1 is a highly conserved DNase that was discovered recently. Mutations in MGME1-coding gene lead to severe mitochondrial syndromes characterized by external ophthalmoplegia, emaciation, and respiratory failure in humans. Unlike many other nucleases that are distributed in multiple cellular organelles, human MGME1 is a mitochondria-specific nuclease; therefore, it can serve as an ideal target for treating related syndromes. Here, we report one HsMGME1-Mn(2+) complex and three different HsMGME1-DNA complex structures. In combination with in vitro cleavage assays, our structures reveal the detailed molecular basis for substrate DNA binding and/or unwinding by HsMGME1. Besides the conserved two-cation-assisted catalytic mechanism, structural analysis of HsMGME1 and comparison with homologous proteins also clarified substrate binding and cleavage directionalities of the DNA double-strand break repair complexes RecBCD and AddAB. Oxford University Press 2018-11-16 2018-09-21 /pmc/articles/PMC6237815/ /pubmed/30247721 http://dx.doi.org/10.1093/nar/gky855 Text en © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Structural Biology
Yang, Chun
Wu, Ruiqi
Liu, Hehua
Chen, Yiqing
Gao, Yanqing
Chen, Xi
Li, Yangyang
Ma, Jinbiao
Li, Jixi
Gan, Jianhua
Structural insights into DNA degradation by human mitochondrial nuclease MGME1
title Structural insights into DNA degradation by human mitochondrial nuclease MGME1
title_full Structural insights into DNA degradation by human mitochondrial nuclease MGME1
title_fullStr Structural insights into DNA degradation by human mitochondrial nuclease MGME1
title_full_unstemmed Structural insights into DNA degradation by human mitochondrial nuclease MGME1
title_short Structural insights into DNA degradation by human mitochondrial nuclease MGME1
title_sort structural insights into dna degradation by human mitochondrial nuclease mgme1
topic Structural Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237815/
https://www.ncbi.nlm.nih.gov/pubmed/30247721
http://dx.doi.org/10.1093/nar/gky855
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