The ber necessities: the repair of dna damage in human-adapted bacterial pathogens

KEY POINTS * Base excision repair (BER) is a highly conserved process that primarily repairs oxidative DNA damage, and human-adapted bacterial pathogens have evolved specialized mechanisms

for BER. * _Mycobacterium tuberculosis_ displays striking redundancy in the enzymes that prevent incorporation of oxidized guanines into the DNA backbone and excise nucleotides mispaired

with this damaged base. * By contrast, _Helicobacter pylori_, which inhabits the gastric mucosa, has a minimal complement of BER enzymes. A network of enzymes recognize and repair DNA damage

by BER in _Neisseria meningitidis_. * Expression of the BER enzymes is constitutive in _Neisseria meningitidis_, which might reflect the high selective pressure of oxidative stress in its

habitat in the aerobic upper airways. * Further work is required to understand mechanisms of BER in other pathogens and related human commensal species, which should provide insights into

whether specialization in BER contributes to colonization and/or human disease. ABSTRACT During colonization and disease, bacterial pathogens must survive the onslaught of the host immune

system. A key component of the innate immune response is the generation of reactive oxygen and nitrogen species by phagocytic cells, which target and disrupt pathogen molecules, particularly

DNA, and the base excision repair (BER) pathway is the most important mechanism for the repair of such oxidative DNA damage. In this Review, we discuss how the human-specific pathogens

_Mycobacterium tuberculosis_, _Helicobacter pylori_ and _Neisseria meningitidis_ have evolved specialized mechanisms of DNA repair, particularly their BER pathways, compared with model

organisms such as _Escherichia coli_. This specialization in DNA repair is likely to reflect the distinct niches occupied by these important human pathogens in the host. Access through your

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BEING VIEWED BY OTHERS BACTERIAL DNA EXCISION REPAIR PATHWAYS Article 24 February 2022 THE PUTATIVE ERROR PRONE POLYMERASE _REV1_ MEDIATES DNA DAMAGE AND DRUG RESISTANCE IN _CANDIDA

ALBICANS_ Article Open access 29 November 2024 THE ALPK1/TIFA/NF-ΚB AXIS LINKS A BACTERIAL CARCINOGEN TO R-LOOP-INDUCED REPLICATION STRESS Article Open access 09 October 2020 REFERENCES *

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(2006). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS Work in C.M.T.'s laboratory is supported by a Wellcome Trust Senior Investigator Award, the Medical Research

Council and Action Medical Research. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, OX1 3RE, UK Stijn van

der Veen & Christoph M. Tang Authors * Stijn van der Veen View author publications You can also search for this author inPubMed Google Scholar * Christoph M. Tang View author

publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Christoph M. Tang. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare

no competing financial interests. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR

TABLE 1 GLOSSARY * Apurinic or apyrimidinic (AP) sites Regions of the DNA that lack nucleobases, generally as a result of DNA damage, spontaneous loss or inefficient DNA repair. * Reactive

oxygen species (ROS). Reactive molecules that contain oxygen (such as superoxide, hydrogen peroxide and hydroxyl radicals), which damage macromolecules such as DNA, proteins and lipids. *

Reactive nitrogen species (RNS). Nitrogen-containing oxides, such as peroxynitrite and nitric oxide radicals, which are highly reactive molecules that damage DNA and proteins through

oxidation and nitrosation reactions. * Phagocytosis The mechanism by which phagocytes, such as macrophages and neutrophils, engulf and destroy microorganisms, foreign material and cellular

debris. * Respiratory burst Rapid release of reactive oxygen species and reactive nitrogen species from immune cells, such as macrophages and neutrophils, to attack invading microorganisms.

It is initiated by the NADPH-dependent oxidase that converts oxygen into superoxide, which subsequently reacts with other molecules such as nitric oxide to form the highly reactive oxidants

peroxynitrite and hydroxyl radials. * Activated neutrophils and macrophages Neutrophils and macrophages that undergo morphological changes following triggers (such as cytokines) and that are

able to extend pseudopods that assist phagocytosis. In addition, they can rapidly release reactive oxygen species and reactive nitrogen species in a 'respiratory burst', thereby

killing engulfed microorganisms. * Superoxide anions (O2−). A common reactive form of oxygen that is generated when molecular oxygen gains an electron. It is a common intermediate in

biological processes and is generated by phagocytes to kill microorganisms in a 'respiratory burst'. * Phagosome Intracellular compartment of a phagocyte that contains phagocytised

microorganisms, foreign material or cellular debris. * Chronic granulomatous disease (CGD). A genetic deficiency of phagocyte oxidase components that is characterized by recurrent

infections. * Hydroxyl radicals (OH•). Highly reactive oxygen-containing molecules that cause severe damage to macromolecules. They are produced by phagocytes through the conversion of water

into superoxide and hydrogen peroxide to kill microorganisms in a 'respiratory burst'. * Fenton reaction Reaction between hydrogen peroxide and iron salts, mostly via iron–sulfur

protein clusters, which generates hydroxyl radicals. * Peroxynitrite (ONOO−). A highly reactive molecule that damages macromolecules, such as DNA and proteins, through oxidation and

nitrosation reactions. In phagocytes, it is produced during the 'respiratory burst' through the reaction of superoxide with nitric oxide. * Deamination Removal of an amine group

from nucleobases, amino acids or other molecules. * Alkylation Transfer of alkyl groups, such as a methyl group or chains with more carbons, between molecules. * β-elimination Cleavage of

the DNA backbone at the 3′ end of an apurinic or apyrimidinic site by a bifunctional DNA glycosylase after removal of a damaged nucleobase. Cleavage produces a 3′-unsaturated aldehyde and a

5′-phosphate group. * γ-elimination Cleavage of the DNA backbone at the 5′ end of an apurinic or apyrimidinic (AP) site by a bifunctional DNA glycosylase. Cleavage removes the AP site and

leaves a phosphate group at both termini. * SOS response An inducible pathway in bacteria that is activated on the accumulation of single-stranded DNA as a result of DNA damage or the

collapse of replication forks. This response typically involves DNA repair proteins and translesion DNA polymerases. * UvrABC complex A multicomponent enzyme complex that has endonucleolytic

activity and is involved in the nucleotide excision repair pathway. * Holliday junction An assembly of four DNA strands that forms during certain types of genetic recombination. *

Hypoxanthine A deamination product of adenine that is highly mutagenic owing to its ability to base-pair with cytosine and adenine during replication. * Ethenocytosine A highly mutagenic

adduct that is formed by the alkylation of cytosine. * Phase variation A heritable change in the level of expression of a protein. It often occurs through an alteration in repetitive DNA

sequences. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE van der Veen, S., Tang, C. The BER necessities: the repair of DNA damage in human-adapted

bacterial pathogens. _Nat Rev Microbiol_ 13, 83–94 (2015). https://doi.org/10.1038/nrmicro3391 Download citation * Published: 12 January 2015 * Issue Date: February 2015 * DOI:

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