Dataset Information

The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides.

ABSTRACT: The X family is one of the eight families of DNA polymerases (dPols) and members of this family are known to participate in the later stages of Base Excision Repair. Many prokaryotic members of this family possess a Polymerase and Histidinol Phosphatase (PHP) domain at their C-termini. The PHP domain has been shown to possess 3'-5' exonuclease activity and may represent the proofreading function in these dPols. PolX from Staphylococcus aureus also possesses the PHP domain at the C-terminus, and we show that this domain has an intrinsic Mn²⁺ dependent 3'-5' exonuclease capable of removing misincorporated dNMPs from the primer. The misincorporation of oxidized nucleotides such as 8oxodGTP and rNTPs are known to be pro-mutagenic and can lead to genomic instability. Here, we show that the PHP domain aids DNA replication by the removal of misincorporated oxidized nucleotides and rNMPs. Overall, our study shows that the proofreading activity of the PHP domain plays a critical role in maintaining genomic integrity and stability. The exonuclease activity of this enzyme can, therefore, be the target of therapeutic intervention to combat infection by methicillin-resistant-Staphylococcus-aureus.

SUBMITTER: Nagpal S

PROVIDER: S-EPMC7893174 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides.

Nagpal Shilpi S Nair Deepak T DT

Scientific reports 20210218 1

The X family is one of the eight families of DNA polymerases (dPols) and members of this family are known to participate in the later stages of Base Excision Repair. Many prokaryotic members of this family possess a Polymerase and Histidinol Phosphatase (PHP) domain at their C-termini. The PHP domain has been shown to possess 3'-5' exonuclease activity and may represent the proofreading function in these dPols. PolX from Staphylococcus aureus also possesses the PHP domain at the C-terminus, and ...[more]

PMID: 33603016

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Project description:Staphylococcus aureus is a major human pathogen that causes a variety of illnesses, ranging from minor skin and soft tissue infections to more severe systemic infections. Although the primary host immune response can typically clear bacterial infections, S. aureus is uniquely resistant to inflammation. For instance, our laboratory has determined that S. aureus is highly resistant to nitric oxide (NO⋅), an important component of the innate immune response that plays a role in both immunomodulatory and antibacterial processes. Additionally, NO⋅ and its derivatives can cause damage to S. aureus DNA, more specifically, deamination and/or oxidation of DNA bases; however, regulation and repair mechanisms of DNA in S. aureus are understudied. Thus, we hypothesize that several DNA repair mechanisms may account for the replication fidelity of S. aureus and may contribute to fitness in the presence of NO⋅. Here, we show the role of several DNA repair mechanisms in S. aureus. More specifically, we found that recombinational repair genes recJ, recG, and polA may play a role in the repair of NO⋅-induced replication fork collapses. We also show the role of the base excision repair pathway protein, MutY, in reducing NO⋅-mediated mutagenesis. Overall, our results suggest that NO⋅ leads to DNA damage, which subsequently induces the activity of several DNA repair pathways, contributing to the replication fidelity and fitness of S. aureus.IMPORTANCEPathogenic bacteria must evolve various mechanisms in order to evade the host immune response that they are infecting. One aspect of the primary host immune response to an infection is the production of an inflammatory effector component, nitric oxide (NO⋅). Staphylococcus aureus has uniquely evolved a diverse array of strategies to circumvent the inhibitory activity of nitric oxide. One such mechanism by which S. aureus has evolved allows the pathogen to survive and maintain its genomic integrity in this environment. For instance, here, our results suggest that S. aureus employs several DNA repair pathways to ensure replicative fitness and fidelity under NO⋅ stress. Thus, our study presents evidence of an additional strategy that allows S. aureus to evade the cytotoxic effects of host NO⋅.

Dataset Information

The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides.

Publications

The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides.

Similar Datasets

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