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.
- Lovett ST. "Template-switching during replication fork repair in bacteria." DNA Repair (Amst). 2017 Aug;56:118-128.
- Laranjo LT, Gross SJ, Zeiger DM, Lovett ST. "SSB recruitment of Exonuclease I aborts template-switching in Escherichia coli." DNA Repair(Amst). 2017 Sep;57:12-16.
- Cooper DL and Lovett ST (2016). "Recombinational branch migration by the RadA/Sms paralog of RecA in Escherichia coli." Elife. 2016 Feb 4;5. pii: e10807..
Cooper DL, Lovett ST (2016). "Genetic analysis of Escherichia coli RadA: functional motifs and genetic interactions." Mol Microbiol 95(5): 769-779.
- Brown LT, Sutera VA Jr, Zhou S, Weitzel CS, Cheng Y, Lovett ST. (2015) Connecting Replication and Repair: YoaA, a Helicase-Related Protein, Promotes Azidothymidine Tolerance through Association with Chi, an Accessory Clamp Loader Protein. PLoS Genet. 2015 Nov 6;11(11):e1005651.
- Anand RP, Lovett ST, Haber JE (2013). "Break-induced DNA replication." Cold Spring Harb Perspect Biol 5(12): a010397.
- Lovett ST (2012). "Biochemistry: A glimpse of molecular competition." Nature 491(7423): 198-200.
- Seier T, Zilberberg G, Zeiger DM, Lovett ST (2012). "Azidothymidine and other chain terminators are mutagenic for template-switch-generated genetic mutations." Proc Natl Acad Sci USA 109(16): 6171-6174.
- Zhao F, Weitzel CS, Gao Y, Browdy HM, Shi J, Lin HC, Lovett ST, Xu B (2011). "beta-Galactosidase-instructed formation of molecular nanofibers and a hydrogel." Nanoscale 3(7): 2859-2861.
- Seier T, Padgett DR, Zilberberg G, Sutera VA Jr, Toha N, Lovett ST (2011). Insights into mutagenesis using Escherichia coli chromosomal lacZ strains that enable detection of a wide spectrum of mutational events. Genetics. 2011 Jun;188(2):247-62.
- 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). Phenotypic landscape of a bacterial cell. Cell. 2011 Jan 7;144(1):143-56.
- Cooper DL, Lovett ST (2011). Toxicity and tolerance mechanisms for azidothymidine, a replication gap-promoting agent, in Escherichia coli. DNA Repair (Amst). 2011 Mar 7;10(3):260-70.
- Merrikh H, Ferrazzoli AE, Lovett ST (2009). Growth phase and (p)ppGpp control of IraD, a regulator of RpoS stability, in Escherichia coli. J Bacteriol. 2009 Dec;191(24):7436-46.
- Persky NS, Ferullo DJ, Cooper DL, Moore HR, Lovett ST (2009). The ObgE/CgtA GTPase influences the stringent response to amino acid starvation in Escherichia coli. Mol Microbiol. 2009 Jul;73(2):253-66.
- Molt KL, Sutera VA, Moore KK, Lovett ST (2009). A Role for Non-essential Domain II of Initiator Protein DnaA in Replication Control. Genetics. 2009 Sep;183(1):39-49..
- Handa N, Morimatsu K, Lovett ST, Kowalczykowski SC (2009). Reconstitution of initial steps of dsDNA break repair by the RecF pathway of E. coli. Genes Dev.2009 May 15;23(10):1234-45.
- Ferullo DJ, Cooper DL, Moore HR, Lovett ST. (2009) Cell cycle synchronization of Escherichia coli using the stringent response, with fluorescence labeling assays for DNA content and replication. Methods. 2009 May; 48(1):8-13.
- Merrikh H, Ferrazzoli AE, Bougdour A, Olivier-Mason A, Lovett ST. (2009) A DNA damage response in Escherichia coli involving the alternative sigma factor, RpoS. Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):611-6. 2009.
- Persky NS, Lovett ST (2008). Mechanisms of Recombination: Lessons from E. coli. Crit Rev Biochem Mol Biol.2008;43(6):347-70.
- Ferullo DJ, Lovett ST (2008). The stringent response and cell cycle arrest in Escherichia coli. Plos Genet. 2008;4(12):e1000300.
- Lovett ST (2007). Polymerase switching in DNA replication. Mol Cell. 2007;27(4):523-6.
- Foti JJ, Persky NS, Ferullo DJ, Lovett ST (2007). Chromosome segregation control by Escherichia coli ObgE GTPase. Mol Microbiol. 2007;65(2):569-81.
- Dutra BE, Sutera VA, Jr., Lovett ST (2007). RecA-independent recombination is efficient but limited by exonucleases. Proc Natl Acad Sci U S A.2007;104(1):216-21.
- Sutera VA, Jr., Lovett ST (2006). The role of replication initiation control in promoting survival of replication fork damage. Mol Microbiol.2006;60(1):229-39.
- Lovett ST (2006). Microbiology: Resurrecting a broken genome. Nature. 2006.
- Lovett ST (2006). Replication arrest-stimulated recombination: Dependence on the RecA paralog, RadA/Sms and translesion polymerase, DinB. DNA Repair (Amst). 2006.
- Han ES, Cooper DL, Persky NS, Sutera VA, Jr., Whitaker RD, Montello ML, et al (2006). RecJ exonuclease: substrates, products and interaction with SSB. Nucleic Acids Res. 2006;34(4):1084-91.
- Goldfless SJ, Morag AS, Belisle KA, Sutera VA, Jr., Lovett ST (2006). DNA Repeat Rearrangements Mediated by DnaK-Dependent Replication Fork Repair. Mol Cell. 2006;21(5):595-604.
- Dutra BE, Lovett ST (2006). Cis and trans-acting effects on a mutational hotspot involving a replication template switch. J Mol Biol.2006;356(2):300-11.
- Lovett ST (2005). Filling the gaps in replication restart pathways. Mol Cell. 2005;17(6):751-2.
- Foti JJ, Schienda J, Sutera VA, Jr., Lovett ST (2005). A bacterial G protein-mediated response to replication arrest. Mol Cell. 2005;17(4):549-60.
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