Apr 5, 2020

Mutation of Conserved Mre11 Residues Alter Protein Dynamics to Separate Nuclease Functions

Journal of Molecular Biology
Samiur RahmanMichael P Latham

Abstract

Naked and protein-blocked DNA ends occur naturally during immune cell development, meiosis, and at telomeres as well as from aborted topoisomerase reactions, collapsed replication forks, and other stressors. Damaged DNA ends are dangerous in cells and if left unrepaired can lead to genomic rearrangement, loss of genetic information, and eventually cancer. Mre11 is part of the Mre11-Rad50-Nbs1 complex that recognizes DNA double-strand breaks and has exonuclease and endonuclease activities that help to initiate the repair processes to resolve these broken DNA ends. In fact, these activities are crucial for proper DNA damage repair pathway choice. Here, using Pyrococcus furiosus Mre11, we question how two Mre11 separation of function mutants - one previously described but the second first described here - maintain endonuclease activity in the absence of exonuclease activity. To start, we performed solution state NMR experiments to assign the side chain methyl groups of the 64 kDa Mre11 nuclease and capping domains, which allowed us to describe the structural differences between Mre11 bound to exo- and endonuclease substrates. Then, through biochemical and biophysical characterization, including NMR structural and dynamics studies,...Continue Reading

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Mentioned in this Paper

MRE11A protein, human
DNA Repair
DNA Replication
Structure
DNA Breaks, Double-Stranded
DNA Sequence Rearrangement
Telomere
T Cell Development Involved in Immune Response
DNA End Binding
Nuclease

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