Abraham S. and Gertrude Burg Professor of Microbiology
Mechanisms of DNA repair and mutation avoidance
All organisms must preserve the integrity of their genomes. In humans, genetic instability is associated with cancer and aging. Our laboratory seeks to understand the fundamental mechanisms by which cells preserve genetic information by the study of DNA damage repair and mutation avoidance in the model organism Escherichia coli. In addition, we have recently begun to ask how cell cycle events including DNA replication and chromosome segregation are coupled to cellular physiology and to the status of the chromosome. We employ genetics, molecular biology, cell biology, and biochemistry in the study of these pathways.
Replication fork repair and coordination with cell cycle: Some of our studies in E. coli address the mechanism of replication fork repair and its integration with the bacterial cell cycle. We are particularly interested in how recombination reactions are integrated and regulated in the disassembly and reassembly of the replication fork, how the organization of the chromosome influences fork repair or whether the sensing of fork damage triggers control of cell division, fork stabilization and replication initiation. We have discovered a GTPase protein that may couple cell division or chromosome segregation with events at the replication fork and this protein is the subject of genetic and biochemical analysis. We can provoke the accumulation of replication gaps by treatment with the chain-terminating drug, azidothymidine—we have identified and are studying several new repair factors that promote tolerance of the drug, as well as pathways that regulate them. We also investigate how cellular nutrition impacts the capacity for replication and repair, as well as structure of the bacterial chromosome.
Mutational hotspots, exonucleases and mutation avoidance: A class of mutational hotspots occurs by misalignment of DNA strands during replication. We have studied chromosomal rearrangements that occur as a result of this aberrant replication and have found additional factors that may promote or inhibit such events. We have identified a potent mutational hotspot that promotes frequent switching between alterative replication templates. We are examining cis- and trans-acting factors, including exonucleases that control these “template-switch” hotspot mutations in E. coli.
- DNA polymerase III protein, HolC, helps resolve replication/transcription conflicts. Lovett ST. Microb Cell. 2021 May 6;8(6):143-145. doi: 10.15698/mic2021.06.753.
- The Role of Replication Clamp-Loader Protein HolC of Escherichia coli in Overcoming Replication/Transcription Conflicts. Cooper DL, Harada T, Tamazi S, Ferrazzoli AE, Lovett ST. mBio. 2021 Mar 9;12(2):e00184-21.
- DNA damage-signaling, homologous recombination and genetic mutation induced by 5-azacytidine and DNA-protein crosslinks in Escherichia coli. Klaric JA, Glass DJ, Perr EL, Reuven AD, Towne MJ, Lovett ST. Mutat Res. 2021 Jan-Jun;822:111742.
- Genetic Analysis of DinG Family Helicase YoaA and Its Interaction with Replication Clamp Loader Protein HolC in Escherichia coli. Sutera VA, Sass TH, Leonard SE, Wu L, Glass DJ, Giordano GG, Zur Y, Lovett ST. J Bacteriol. 2021 Aug 20;203(18):e0022821.
- Alternative complexes formed by the Escherichia coli clamp loader accessory protein HolC (x) with replication protein HolD (ψ) and repair protein YoaA. Sutera VA, Weeks SJ, Dudenhausen EE, Baggett HBR, Shaw MC, Brand KA, Glass DJ, Bloom LB, Lovett ST. DNA Repair (Amst). 2021 Apr;100:103006.
- Identifying Small Molecules That Promote Quasipalindrome-Associated Template-Switch Mutations in Escherichia coli. Klaric JA, Perr EL, Lovett ST. G3 (Bethesda). 2020 May 4;10(5):1809-1815. doi: 10.1534/g3.120.401106.
- Frequent template switching in postreplication gaps: suppression of deleterious consequences by the Escherichia coli Uup and RadD proteins. Romero ZJ, Armstrong TJ, Henrikus SS, Chen SH, Glass DJ, Ferrazzoli AE, Wood EA, Chitteni-Pattu S, van Oijen AM, Lovett ST, Robinson A, Cox MM. Nucleic Acids Res. 2020 Jan 10;48(1):212-230. doi: 10.1093/nar/gkz960.
- Structure-Activity Relationship of Peptide-Conjugated Chloramphenicol for Inhibiting Escherichia coli. Wang J, Shy A, Wu D, Cooper DL, Xu J, He H, Zhan W, Sun S, Lovett ST, Xu B. J Med Chem. 2019 Nov 27;62(22):10245-10257.
- Diglycine Enables Rapid Intrabacterial Hydrolysis for Activating Anbiotics against Gram-negative Bacteria. Wang J, Cooper DL, Zhan W, Wu D, He H, Sun S, Lovett ST, Xu B. Angew Chem Int Ed Engl. 2019 Jul 29;58(31):10631-10634.
- Between sisters: Watching replication-associated recombinational DNA repair. Lovett ST. J Cell Biol. 2018 Jul 2;217(7):2225-2227. doi: 10.1083/jcb.201805091.
- Stimulation of Replication Template-Switching by DNA-Protein Crosslinks. Laranjo LT, Klaric JA, Pearlman LR, Lovett ST. Genes (Basel). 2018 Dec 27;10(1):14. doi: 10.3390/genes10010014.
- Template-switching during replication fork repair in bacteria. Lovett ST. DNA Repair (Amst). 2017 Aug;56:118-128.
- SSB recruitment of Exonuclease I aborts template-switching in Escherichia coli. Laranjo LT, Gross SJ, Zeiger DM, Lovett ST. DNA Repair(Amst). 2017 Sep;57:12-16.
- Recombinational branch migration by the RadA/Sms paralog of RecA in Escherichia coli. Cooper DL and Lovett ST (2016). Elife. 2016 Feb 4;5. pii: e10807.
- Genetic analysis of Escherichia coli RadA: functional motifs and genetic interactions. Cooper DL, Lovett ST (2016). Mol Microbiol 95(5): 769-779.
- Connecting Replication and Repair: YoaA, a Helicase-Related Protein, Promotes Azidothymidine Tolerance through Association with Chi, an Accessory Clamp Loader Protein. Brown LT, Sutera VA Jr, Zhou S, Weitzel CS, Cheng Y, Lovett ST. (2015) PLoS Genet. 2015 Nov 6;11(11):e1005651.
- Break-induced DNA replication. Anand RP, Lovett ST, Haber JE (2013). Cold Spring Harb Perspect Biol 5(12): a010397.
- Biochemistry: A glimpse of molecular competition. Lovett ST (2012). Nature 491(7423): 198-200.
- Azidothymidine and other chain terminators are mutagenic for template-switch-generated genetic mutations. Seier T, Zilberberg G, Zeiger DM, Lovett ST (2012). Proc Natl Acad Sci USA 109(16): 6171-6174.
- beta-Galactosidase-instructed formation of molecular nanofibers and a hydrogel. Zhao F, Weitzel CS, Gao Y, Browdy HM, Shi J, Lin HC, Lovett ST, Xu B (2011). Nanoscale 3(7): 2859-2861.
- Insights into mutagenesis using Escherichia coli chromosomal lacZ strains that enable detection of a wide spectrum of mutational events. Seier T, Padgett DR, Zilberberg G, Sutera VA Jr, Toha N, Lovett ST (2011). Genetics. 2011 Jun;188(2):247-62.
- Phenotypic landscape of a bacterial cell. Nichols RJ, Sen S, Choo YJ, Beltrao P, Zietek M, Chaba R, Lee S, Kazmierczak KM, Lee KJ, Wong A, Shales M, Lovett S, Winkler ME, Krogan NJ, Typas A, Gross CA (2011). Cell. 2011 Jan 7;144(1):143-56.
- Toxicity and tolerance mechanisms for azidothymidine, a replication gap-promoting agent, in Escherichia coli. Cooper DL, Lovett ST (2011). DNA Repair (Amst). 2011 Mar 7;10(3):260-70.
- Growth phase and (p)ppGpp control of IraD, a regulator of RpoS stability, in Escherichia coli. Merrikh H, Ferrazzoli AE, Lovett ST (2009). J Bacteriol. 2009 Dec;191(24):7436-46.
- The ObgE/CgtA GTPase influences the stringent response to amino acid starvation in Escherichia coli. Persky NS, Ferullo DJ, Cooper DL, Moore HR, Lovett ST (2009). Mol Microbiol. 2009 Jul;73(2):253-66.
- A Role for Non-essential Domain II of Initiator Protein DnaA in Replication Control. Molt KL, Sutera VA, Moore KK, Lovett ST (2009). Genetics. 2009 Sep;183(1):39-49..
- Reconstitution of initial steps of dsDNA break repair by the RecF pathway of E. coli. Handa N, Morimatsu K, Lovett ST, Kowalczykowski SC (2009). Genes Dev.2009 May 15;23(10):1234-45.
- Cell cycle synchronization of Escherichia coli using the stringent response, with fluorescence labeling assays for DNA content and replication. Ferullo DJ, Cooper DL, Moore HR, Lovett ST. (2009) Methods. 2009 May; 48(1):8-13.
- A DNA damage response in Escherichia coli involving the alternative sigma factor, RpoS. Merrikh H, Ferrazzoli AE, Bougdour A, Olivier-Mason A, Lovett ST. (2009)Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):611-6. 2009.
- Mechanisms of Recombination: Lessons from E. coli. Persky NS, Lovett ST (2008). Crit Rev Biochem Mol Biol.2008;43(6):347-70.
- The stringent response and cell cycle arrest in Escherichia coli. Ferullo DJ, Lovett ST (2008). Plos Genet. 2008;4(12):e1000300.
- Polymerase switching in DNA replication. Lovett ST (2007). Mol Cell. 2007;27(4):523-6.
- Chromosome segregation control by Escherichia coli ObgE GTPase. Foti JJ, Persky NS, Ferullo DJ, Lovett ST (2007). Mol Microbiol. 2007;65(2):569-81.
- RecA-independent recombination is efficient but limited by exonucleases. Dutra BE, Sutera VA, Jr., Lovett ST (2007). Proc Natl Acad Sci U S A.2007;104(1):216-21.
- The role of replication initiation control in promoting survival of replication fork damage. Sutera VA, Jr., Lovett ST (2006). Mol Microbiol.2006;60(1):229-39.
- Microbiology: Resurrecting a broken genome. Lovett ST (2006). Nature. 2006.
- Replication arrest-stimulated recombination: Dependence on the RecA paralog, RadA/Sms and translesion polymerase, DinB. Lovett ST (2006). DNA Repair (Amst). 2006.
- RecJ exonuclease: substrates, products and interaction with SSB. Han ES, Cooper DL, Persky NS, Sutera VA, Jr., Whitaker RD, Montello ML, et al (2006). Nucleic Acids Res. 2006;34(4):1084-91.
- DNA Repeat Rearrangements Mediated by DnaK-Dependent Replication Fork Repair. Goldfless SJ, Morag AS, Belisle KA, Sutera VA, Jr., Lovett ST (2006). Mol Cell. 2006;21(5):595-604.
- Cis and trans-acting effects on a mutational hotspot involving a replication template switch. Dutra BE, Lovett ST (2006). J Mol Biol.2006;356(2):300-11.
- Filling the gaps in replication restart pathways. Lovett ST (2005). Mol Cell. 2005;17(6):751-2.
- A bacterial G protein-mediated response to replication arrest. Foti JJ, Schienda J, Sutera VA, Jr., Lovett ST (2005). Mol Cell. 2005;17(4):549-60.
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