Abstract
The DNA repair endonuclease EndoMS/NucS is highly conserved in Archaea and Actinobacteria. This enzyme is able to recognize and cleave dsDNA carrying a mismatched base pair, and its activity is enhanced by the interaction with the sliding clamp of the replisome. Today, EndoMS/NucS has been established as the key protein of a non-canonical mismatch repair (MMR) pathway, acting specifically in the repair of transitions and being essential for maintaining genome stability. Despite having some particularities, such as its lower activity on transversions and the inability to correct indels, EndoMS/NucS meets the main hallmarks of a MMR. Its absence leads to a hypermutator phenotype, a transition-biased mutational spectrum and an increase in homeologous recombination. Interestingly, polymorphic EndoMS/NucS variants with a possible effect in mutation rate have been detected in clinical isolates of the relevant actinobacterial pathogen Mycobacterium tuberculosis. Considering that MMR defects are often associated with the emergence of resistant bacteria, the existence of EndoMS/NucS-defective mutators could have an important role in the acquisition of antibiotic resistance in M. tuberculosis. Therefore, a further understanding of the EndoMS/NucS-mediated non-canonical MMR pathway may reveal new strategies to predict and fight drug resistance. This review is focused on the recent progress in NucS, with special emphasis on its effect on genome stability and evolvability in Actinobacteria.
Highlights
Exogenous and endogenous factors produce damage in DNA that needs to be repaired in order to avoid detrimental effects on the cells, such as mutations and eventually, cell death
The main DNA repair pathways conserved from prokaryotes to eukaryotes include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR) and non-homologous end-joining (NHEJ) [2]
The MMR system has a role in the DNA damage response, recognizing the mismatches generated by the chemical modification of bases due to DNA damaging agents [5]
Summary
Exogenous and endogenous factors produce damage in DNA that needs to be repaired in order to avoid detrimental effects on the cells, such as mutations and eventually, cell death. Analysis of the sequence of NucS from Mycobacterium smegmatis and M. tuberculosis, actinobacterial members of this protein family, has unravelled important details related to the domain arrangement in this protein It contains an N-terminal DNA-binding region, predicted to be the recognition site for the DNA substrate, followed by a C-terminal catalytic region responsible for the cleavage of the DNA, supporting its nuclease enzymatic activity [20]. The crystal structure of the archaeal NucS showed that the N-terminal DNAbinding domain is folded in a unique half-closed β-barrel structure that comprises two layers of anti-parallel sheets (eight β-strands in total plus one additional α-helix) This region is involved in enzyme dimerization, which is required for proper protein folding and stabilization. This attachment is prompted by a huge conformational change in the C-terminal domains, as revealed by structural comparisons between the unbound (apo) and bound form of T. kodakarensis NucS, required for proper recognition, positioning and cleavage of the DNA substrate [29]
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