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Maintaining the Genomic Integrity of Staphylococcus aureus in the Presence of Exogenously Induced DNA Damage

Hurley, Kelly and Richardson, Anthony (2022) Maintaining the Genomic Integrity of Staphylococcus aureus in the Presence of Exogenously Induced DNA Damage. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Abstract

Staphylococcus aureus is a major human pathogen that causes a variety of illnesses ranging from minor skin and soft tissue infections (SSTIs) to more severe systemic infections. Although the primary host immune response can typically clear pathogenic bacterial infections, S. aureus is uniquely resistant to this environment. Our lab has determined that nitric oxide (NO), an important component of the innate immune response that plays a role in both immunomodulatory and antibacterial processes, is the effector to which S. aureus is specifically resistant. Additionally, NO and its derivatives can lead to damage of S. aureus DNA, more specifically, deamination and/or oxidation of DNA bases; however, regulation and repair mechanisms of DNA in S. aureus is understudied. Thus, we hypothesize 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 recombinational repair gene, recG, may play a role in the repair of NO-induced replication fork collapses. We also show a role of base excision repair pathway protein, MutY, in reducing NO-mediated mutagenesis. Lastly, we show the role of the mismatch repair pathway in preventing illegitimate recombination. It is known that MMR proteins prevent RecA-mediated recombination between divergent sequences. S. aureus has three mismatch repair MutS homologues that work alongside an endonuclease, MutL. Only one has been studied and was shown to limit spontaneous mutagenesis but did not appear to have a role in preventing illegitimate homologous recombination. Here we confirm only one MutS homologue, MutS1, contributes to mutagenesis in S. aureus. We also show a role of the MutS1 homologue in preventing illegitimate recombination between divergent sequences. Overall, our results suggest NO leads to DNA damage, which subsequently induces activity of several DNA repair pathways, contributing to the replication fidelity and fitness of S. aureus. Although one mismatch repair homologue contributes to mutagenesis, no other combinatorial homologues play a role.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hurley, Kellykeh186@pitt.edukeh186
Richardson, Anthonyanthony.richardson@pitt.eduanthony.richardson
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRichardson, Anthony R.anthony.richardson@pitt.eduanthony.richardson
Committee MemberMattila, Joshua T.jmattila@pitt.edujmattila
Committee MemberYasin, Mohamed Hamdymhy8@pitt.edumhy8
Date: 12 May 2022
Date Type: Publication
Defense Date: 25 April 2022
Approval Date: 12 May 2022
Submission Date: 22 April 2022
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 43
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Staphylococcus, aureus, S. aureus, DNA repair, nitric oxide, recombination, replication integrity
Date Deposited: 12 May 2022 13:17
Last Modified: 12 May 2022 13:17
URI: http://d-scholarship.pitt.edu/id/eprint/42717

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