Structural insights into DNA degradation by human mitochondrial nuclease MGME1. Issue 20 (21st September 2018)

• Record Type: Journal Article
• Authors: Yang, Chun; Wu, Ruiqi; Liu, Hehua; Chen, Yiqing; Gao, Yanqing; Chen, Xi; Li, Yangyang; Ma, Jinbiao; Li, Jixi; Gan, Jianhua
• Is Part Of: Nucleic acids research. Volume 46:Issue 20(2018)
• Page Start: 11075
• Page End: 11088
• Publication Date: 2018-09-21
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky855
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: 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 Hs MGME1-Mn 2+ complex and three different Hs MGME1-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 Hs MGME1. Besides the conserved two-cation-assisted catalytic mechanism, structural analysis of Hs MGME1 and comparison with homologous proteins also clarified substrate binding and cleavage directionalities of the DNA double-strand break repair complexes RecBCD and AddAB.