Abstract
BackgroundThe genome of the halophilic archaeon Halobacterium salinarum NRC-1 encodes for homologs of MutS and MutL, which are key proteins of a DNA mismatch repair pathway conserved in Bacteria and Eukarya. Mismatch repair is essential for retaining the fidelity of genetic information and defects in this pathway result in the deleterious accumulation of mutations and in hereditary diseases in humans.Methodology/Principal FindingsWe calculated the spontaneous genomic mutation rate of H. salinarum NRC-1 using fluctuation tests targeting genes of the uracil monophosphate biosynthesis pathway. We found that H. salinarum NRC-1 has a low incidence of mutation suggesting the presence of active mechanisms to control spontaneous mutations during replication. The spectrum of mutational changes found in H. salinarum NRC-1, and in other archaea, appears to be unique to this domain of life and might be a consequence of their adaption to extreme environmental conditions. In-frame targeted gene deletions of H. salinarum NRC-1 mismatch repair genes and phenotypic characterization of the mutants demonstrated that the mutS and mutL genes are not required for maintenance of the observed mutation rate.Conclusions/SignificanceWe established that H. salinarum NRC-1 mutS and mutL genes are redundant to an alternative system that limits spontaneous mutation in this organism. This finding leads to the puzzling question of what mechanism is responsible for maintenance of the low genomic mutation rates observed in the Archaea, which for the most part do not have MutS and MutL homologs.
Highlights
DNA mismatch repair (MMR) is the major pathway for the repair of DNA replication errors such as nucleotide mismatches, insertions, and deletions [1]
We determined the genomic mutation rate of the halophilic mesophile, H. salinarum NRC-1, one of the few archaea to encode for a bacterial-like version of the conserved MutS and MutL proteins
We found that H. salinarum NRC-1 mutation rate was similar to that previously calculated for DNA-based microorganisms, with 1.6761023 mutations per genome per replication, suggesting the presence of high fidelity replication machinery in this organism [4,12,28,29,30,31,32]
Summary
DNA mismatch repair (MMR) is the major pathway for the repair of DNA replication errors such as nucleotide mismatches, insertions, and deletions [1]. Defects in the MMR pathway lead to genomic instability that can cause a 10 to 1000-fold increase in spontaneous mutability, meiotic defects in eukaryotes, and tolerance to DNA alkylating agents [1,2,3]. The key proteins of the MMR pathway, MutS and MutL, are highly conserved between Bacteria and Eukarya. MutL is a 68kDa protein that exists as a dimer in solution and is a member of the Bergerat-fold ATPase/kinase family [3,10]. Eukaryotes have multiple homologs of the MutS and MutL proteins that form heterodimers suggesting a more complex system than in bacteria with multiple interactions [1,2]. The genome of the halophilic archaeon Halobacterium salinarum NRC-1 encodes for homologs of MutS and MutL, which are key proteins of a DNA mismatch repair pathway conserved in Bacteria and Eukarya. Mismatch repair is essential for retaining the fidelity of genetic information and defects in this pathway result in the deleterious accumulation of mutations and in hereditary diseases in humans
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