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Principal Investigator: SUSAN THOMAS LOVETT
Organization: BRANDEIS UNIVERSITY
Fiscal Year: 2024
Award: $504,582
Funding agency: National Institute of General Medical Sciences
Project Summary
Replication fork repair is essential for cell survival and stability of genetic material. In humans,
inefficiency of repair is associated with cancer proneness, neurological, immunological,
developmental defects and premature aging. For microbial pathogens, the ability to repair DNA
damage is required for survival of bacterial pathogens and promotes genetic change that can
contribute to antibiotic resistance and persistence of infection.
The long-term goal of our studies is a more complete mechanistic understanding of the repair of
replication forks and how it affects genomic stability. This will be accomplished using the genetic
system of Escherichia coli, whose physiology is well understood. A central interest is how
bacterial cells signal difficulties in replication to facilitate repair and how this is integrated with
other aspects of bacterial growth. By biochemical and genetic analysis, this work will elucidate
how a newly discovered conserved DNA helicase protein, YoaA, interacts with the replisome to
overcome barriers in replication. This study will specifically address the influence of RNA
transcription and DNA protein complexes on replication and genomic instability and what
mechanisms are used to overcome conflicts between replication and transcription machinery.
The regulatory pathway controlled by stringent starvation protein, SspA, will also be explored to
discover how it impacts DNA metabolism.
Because all cells repair DNA in fundamentally similar ways by evolutionarily related pathways,
these studies using microbial model organisms should reveal mechanisms applicable to repair
of DNA in human cells. In addition, because the DNA damage response in microbial pathogens
plays a role in toxin production, antibiotic resistance and persistence of infection, this work could
provide new information important for the treatment of infectious disease.
Terms: <Address><Affect><Aging><Antibiotic Resistance><Bacteria><Bacteria KatF protein><Bacteria rpoS protein><Bacteria sigma factor 38 protein><Bacteria sigma factor KatF protein><Bacteria sigma factor S protein><Base Pairing><Binding><Binding Proteins><Biochemical><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Survival><Cell Viability><Cells><Clampings><Closure by clamp><Coenzyme Q-Cytochrome-c Reductase><Coenzyme QH2-Cytochrome-c Reductase><Complex><Complex III><Copying Processes><Cytochrome b-c2 Oxidoreductase><DNA><DNA Damage><DNA Damage Repair><DNA Helicases><DNA Injury><DNA Molecular Biology><DNA Polymerase III><DNA Polymerase delta><DNA Repair><DNA Replication><DNA Synthesis><DNA Unwinding Proteins><DNA biosynthesis><DNA metabolism><DNA replication fork><DNA unwinding enzyme><DNA-Dependent DNA Polymerase III><DNA-Dependent RNA Polymerases><DNA-Directed RNA Polymerase><Defect><Deoxyribonucleic Acid><Development><Dihydroubiquinone-Cytochrome-c Reductase><Duplicating Processes><E coli><E. coli><Electron Transport Complex III><Escherichia coli><Event><Evolution><Gene Transcription><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Materials><Genetic Transcription><Genetic analyses><Genetic defect><Genome><Genome Instability><Genome Stability><Genomic DNA><Genomic Instability><Genomic Stability><Goals><Gram-Negative Bacteria><Growth><Head><Holoenzymes><Human><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Infection><Information Protection><Interruption><Intracellular Communication and Signaling><Left><Ligand Binding Protein><Ligand Binding Protein Gene><Malignant Neoplasms><Malignant Tumor><Mediating><Microscopic><Modern Man><Molecular Biology><Molecular Interaction><Mutation><Neurologic><Neurological><Non-Polyadenylated RNA><Nucleotides><Organism><Pathogenicity Factors><Pathway interactions><Physiology><Play><Pol III><Premature Aging><Premature aging syndrome><Process><Production><Proliferating><Property><Protein Binding><Protein Biochemistry><Protein/Amino Acid Biochemistry><Proteins><QH(2)-Cytochrome-c Reductase><QH(2)-Ferricytochrome-c Oxidoreductase><RNA><RNA Expression><RNA Gene Products><RNA Polymerases><Reaction><Regulatory Pathway><Resistance to antibiotics><Resistant to antibiotics><Ribonucleic Acid><Ribosomal RNA><Role><RpoS><Signal Transduction><Signal Transduction Systems><Signaling><Site><Starvation><Structure><System><Testing><Tissue Growth><Toxin><Transcript><Transcription><Transcription Activator><Transcription Coactivator><Transcription Factor Coactivator><Transcription Regulation><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Transcriptional Control><Transcriptional Regulation><Ubihydroquinone-Cytochrome-c Reductase><Ubiquinol-Cytochrome-c Reductase><Ubiquinol-ferricytochrome-c oxidoreductase><Ubiquinone-Cytochrome b-c2 Oxidoreductase><Unscheduled DNA Synthesis><Virulence Factors><Visualization><Work><antibiotic drug resistance><antibiotic resistant><bacteria pathogen><bacterial pathogen><biological signal transduction><bound protein><cold shock protein><conflict resolution><developmental><gDNA><genetic analysis><genetic approach><genetic condition><genetic disorder><genetic strategy><genome mutation><helicase><infectious disease treatment><inhibitor><interest><living system><malignancy><microbe pathogen><microbial><microbial pathogen><microorganism><model organism><mutant><neoplasm/cancer><novel><ontogeny><pathogenic bacteria><pathogenic microbe><pathway><prevent><preventing><protein complex><rRNA><rRNA Operon><recruit><repair><repaired><replication fork><response><rho><sigma(38) protein, Bacteria><sigma(S) protein, Bacteria><social role><transcription co-activator><transcription termination><transcriptional co-activator>