Harvard Catalyst Profiles

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Joseph John Loparo, Ph.D.

Other Positions

Available: 10/26/20, Expires: 10/25/21

DNA replication is an essential cellular process that duplicates chromosomes. Chemical damage to DNA poses a potent challenge to genome stability as adducts within the template DNA strand can block DNA replication. Notably, a host of widely used antibiotics result in oxidative DNA damage in bacterial cells, and how bacterial cells cope with this DNA damage underlies the emergence of antibiotics resistance. Our research group studies the molecular mechanisms by which stalled DNA replication is resolved and how these resolution pathways are regulated. Ultimately we aim to translate mechanistic discovery into the development of therapeutics that may attenuate the emergence of antibiotic resistance. We recently discovered an interesting mutation within an error-prone DNA polymerase that compromises its interaction with the replication machinery. Currently, we are using a multi-angled approach to determine if this mutation attenuates the emergence of antibiotic resistance.

Potential research projects include the following:

  1. Characterization of antibiotic-induced mutagenesis
  2. In vitro reconstitution of error-prone DNA repair
  3. Structural characterization of protein-protein interactions within stalled replication machinery and repair complexes.

An interested student researcher will work in the laboratory (HMS Quad) under the daily guidance of an instructor and will have the opportunity to meet regularly with the PI. Interested students of all research experience levels are encouraged to apply.

The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. R03AI159062 (LOPARO, JOSEPH JOHN) Mar 8, 2021 - Feb 28, 2023
    Validating a potential interaction between error-prone polymerases and SSB as a therapeutic target for Mycobacterium tuberculosis
    Role: Principal Investigator
  2. R01GM115487 (LOPARO, JOSEPH J.) Sep 1, 2015 - Apr 30, 2024
    Visualizing DNA break repair: single-molecule studies of non-homologous end joining
    Role: Principal Investigator
  3. R01GM114065 (LOPARO, JOSEPH JOHN) May 15, 2015 - Dec 31, 2024
    Regulation of translesion synthesis by the bacterial replisome
    Role: Principal Investigator

Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
  1. Karunatilaka KS, Filman DJ, Strauss M, Loparo JJ, Hogle JM. Real-Time Imaging of Polioviral RNA Translocation across a Membrane. mBio. 2021 02 23; 12(1). PMID: 33622727.
    Citations:    Fields:    
  2. Stinson BM, Loparo JJ. Repair of DNA Double-Strand Breaks by the Nonhomologous End Joining Pathway. Annu Rev Biochem. 2021 Feb 08. PMID: 33556282.
    Citations:    Fields:    
  3. Carney SM, Moreno AT, Piatt SC, Cisneros-Aguirre M, Lopezcolorado FW, Stark JM, Loparo JJ. XLF acts as a flexible connector during non-homologous end joining. Elife. 2020 12 08; 9. PMID: 33289484.
    Citations: 3     Fields:    Translation:AnimalsCells
  4. Hernandez AJ, Lee SJ, Chang S, Lee JA, Loparo JJ, Richardson CC. Catalytically inactive T7 DNA polymerase imposes a lethal replication roadblock. J Biol Chem. 2020 07 10; 295(28):9542-9550. PMID: 32430399.
    Citations:    Fields:    Translation:Cells
  5. Stinson BM, Moreno AT, Walter JC, Loparo JJ. A Mechanism to Minimize Errors during Non-homologous End Joining. Mol Cell. 2020 03 05; 77(5):1080-1091.e8. PMID: 31862156.
    Citations: 13     Fields:    Translation:AnimalsCells
  6. Chang S, Naiman K, Thrall ES, Kath JE, Jergic S, Dixon NE, Fuchs RP, Loparo JJ. A gatekeeping function of the replicative polymerase controls pathway choice in the resolution of lesion-stalled replisomes. Proc Natl Acad Sci U S A. 2019 12 17; 116(51):25591-25601. PMID: 31796591.
    Citations: 5     Fields:    Translation:Cells
  7. Heustis RJ, Venkatesh MJ, Gutlerner JL, Loparo JJ. Embedding academic and professional skills training with experimental-design chalk talks. Nat Biotechnol. 2019 12; 37(12):1523-1527. PMID: 31796928.
    Citations:    Fields:    
  8. Kim H, Yen L, Wongpalee SP, Kirshner JA, Mehta N, Xue Y, Johnston JB, Burlingame AL, Kim JK, Loparo JJ, Jacobsen SE. The Gene-Silencing Protein MORC-1 Topologically Entraps DNA and Forms Multimeric Assemblies to Cause DNA Compaction. Mol Cell. 2019 08 22; 75(4):700-710.e6. PMID: 31442422.
    Citations: 5     Fields:    Translation:AnimalsCells
  9. Piatt SC, Loparo JJ, Price AC. The Role of Noncognate Sites in the 1D Search Mechanism of EcoRI. Biophys J. 2019 06 18; 116(12):2367-2377. PMID: 31113551.
    Citations: 1     Fields:    Translation:Cells
  10. Drabek AA, Loparo JJ, Blacklow SC. A Flow-Extension Tethered Particle Motion Assay for Single-Molecule Proteolysis. Biochemistry. 2019 05 21; 58(20):2509-2518. PMID: 30946563.
    Citations: 1     Fields:    Translation:HumansCells
  11. Catipovic MA, Bauer BW, Loparo JJ, Rapoport TA. Protein translocation by the SecA ATPase occurs by a power-stroke mechanism. EMBO J. 2019 05 02; 38(9). PMID: 30877095.
    Citations: 11     Fields:    Translation:Cells
  12. Klein HL, Ang KKH, Arkin MR, Beckwitt EC, Chang YH, Fan J, Kwon Y, Morten MJ, Mukherjee S, Pambos OJ, El Sayyed H, Thrall ES, Vieira-da-Rocha JP, Wang Q, Wang S, Yeh HY, Biteen JS, Chi P, Heyer WD, Kapanidis AN, Loparo JJ, Strick TR, Sung P, Van Houten B, Niu H, Rothenberg E. Guidelines for DNA recombination and repair studies: Mechanistic assays of DNA repair processes. Microb Cell. 2019 Jan 07; 6(1):65-101. PMID: 30652106.
    Citations: 3     
  13. Graham TGW, Carney SM, Walter JC, Loparo JJ. A single XLF dimer bridges DNA ends during nonhomologous end joining. Nat Struct Mol Biol. 2018 09; 25(9):877-884. PMID: 30177755.
    Citations: 10     Fields:    Translation:HumansAnimalsCells
  14. Kim H, Loparo JJ. Observing Bacterial Chromatin Protein-DNA Interactions by Combining DNA Flow-Stretching with Single-Molecule Imaging. Methods Mol Biol. 2018; 1837:277-299. PMID: 30109616.
    Citations: 1     Fields:    Translation:Cells
  15. Thrall ES, Kath JE, Chang S, Loparo JJ. Single-molecule imaging reveals multiple pathways for the recruitment of translesion polymerases after DNA damage. Nat Commun. 2017 12 18; 8(1):2170. PMID: 29255195.
    Citations: 11     Fields:    Translation:Cells
  16. Song D, Rodrigues K, Graham TGW, Loparo JJ. A network of cis and trans interactions is required for ParB spreading. Nucleic Acids Res. 2017 Jul 07; 45(12):7106-7117. PMID: 28407103.
    Citations: 13     Fields:    Translation:Cells
  17. Graham TGW, Walter JC, Loparo JJ. Ensemble and Single-Molecule Analysis of Non-Homologous End Joining in Frog Egg Extracts. Methods Enzymol. 2017; 591:233-270. PMID: 28645371.
    Citations: 5     Fields:    Translation:AnimalsCells
  18. Lee DF, Lu J, Chang S, Loparo JJ, Xie XS. Mapping DNA polymerase errors by single-molecule sequencing. Nucleic Acids Res. 2016 07 27; 44(13):e118. PMID: 27185891.
    Citations: 13     Fields:    Translation:HumansCells
  19. Graham TG, Walter JC, Loparo JJ. Two-Stage Synapsis of DNA Ends during Non-homologous End Joining. Mol Cell. 2016 Mar 17; 61(6):850-8. PMID: 26990988.
    Citations: 39     Fields:    Translation:HumansCells
  20. Song D, Graham TG, Loparo JJ. A general approach to visualize protein binding and DNA conformation without protein labelling. Nat Commun. 2016 Mar 08; 7:10976. PMID: 26952553.
    Citations: 10     Fields:    Translation:Cells
  21. Kim H, Loparo JJ. Multistep assembly of DNA condensation clusters by SMC. Nat Commun. 2016 Jan 04; 7:10200. PMID: 26725510.
    Citations: 22     Fields:    Translation:Cells
  22. Kath JE, Chang S, Scotland MK, Wilbertz JH, Jergic S, Dixon NE, Sutton MD, Loparo JJ. Exchange between Escherichia coli polymerases II and III on a processivity clamp. Nucleic Acids Res. 2016 Feb 29; 44(4):1681-90. PMID: 26657641.
    Citations: 14     Fields:    Translation:Cells
  23. Gambino S, Mousley B, Cathcart L, Winship J, Loparo JJ, Price AC. A single molecule assay for measuring site-specific DNA cleavage. Anal Biochem. 2016 Feb 15; 495:3-5. PMID: 26655389.
    Citations: 2     Fields:    Translation:Cells
  24. Scotland MK, Heltzel JM, Kath JE, Choi JS, Berdis AJ, Loparo JJ, Sutton MD. A Genetic Selection for dinB Mutants Reveals an Interaction between DNA Polymerase IV and the Replicative Polymerase That Is Required for Translesion Synthesis. PLoS Genet. 2015 Sep; 11(9):e1005507. PMID: 26352807.
    Citations: 16     Fields:    Translation:Cells
  25. Gordon WR, Zimmerman B, He L, Miles LJ, Huang J, Tiyanont K, McArthur DG, Aster JC, Perrimon N, Loparo JJ, Blacklow SC. Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. Dev Cell. 2015 Jun 22; 33(6):729-36. PMID: 26051539.
    Citations: 86     Fields:    Translation:HumansAnimalsCells
  26. Price AC, Pilkiewicz KR, Graham TGW, Song D, Eaves JD, Loparo JJ. DNA motion capture reveals the mechanical properties of DNA at the mesoscale. Biophys J. 2015 May 19; 108(10):2532-2540. PMID: 25992731.
    Citations: 7     Fields:    
  27. Song D, Loparo JJ. Building bridges within the bacterial chromosome. Trends Genet. 2015 Mar; 31(3):164-73. PMID: 25682183.
    Citations: 22     Fields:    Translation:Cells
  28. Broedersz CP, Wang X, Meir Y, Loparo JJ, Rudner DZ, Wingreen NS. Condensation and localization of the partitioning protein ParB on the bacterial chromosome. Proc Natl Acad Sci U S A. 2014 Jun 17; 111(24):8809-14. PMID: 24927534.
    Citations: 38     Fields:    Translation:Cells
  29. Graham TG, Wang X, Song D, Etson CM, van Oijen AM, Rudner DZ, Loparo JJ. ParB spreading requires DNA bridging. Genes Dev. 2014 Jun 01; 28(11):1228-38. PMID: 24829297.
    Citations: 74     Fields:    Translation:Cells
  30. Kath JE, Jergic S, Heltzel JM, Jacob DT, Dixon NE, Sutton MD, Walker GC, Loparo JJ. Polymerase exchange on single DNA molecules reveals processivity clamp control of translesion synthesis. Proc Natl Acad Sci U S A. 2014 May 27; 111(21):7647-52. PMID: 24825884.
    Citations: 35     Fields:    Translation:Cells
  31. Tanner NA, Tolun G, Loparo JJ, Jergic S, Griffith JD, Dixon NE, van Oijen AM. E. coli DNA replication in the absence of free ß clamps. EMBO J. 2011 May 04; 30(9):1830-40. PMID: 21441898.
    Citations: 22     Fields:    Translation:Cells
  32. Loparo JJ, Kulczyk AW, Richardson CC, van Oijen AM. Simultaneous single-molecule measurements of phage T7 replisome composition and function reveal the mechanism of polymerase exchange. Proc Natl Acad Sci U S A. 2011 Mar 01; 108(9):3584-9. PMID: 21245349.
    Citations: 53     Fields:    Translation:Cells
  33. Kulczyk AW, Tanner NA, Loparo JJ, Richardson CC, van Oijen AM. Direct observation of enzymes replicating DNA using a single-molecule DNA stretching assay. J Vis Exp. 2010 Mar 23; (37). PMID: 20332766.
    Citations: 5     Fields:    Translation:Cells
  34. van Oijen AM, Loparo JJ. Single-molecule studies of the replisome. Annu Rev Biophys. 2010; 39:429-48. PMID: 20462378.
    Citations: 20     Fields:    Translation:AnimalsCells
  35. Tanner NA, Loparo JJ, van Oijen AM. Visualizing Single-molecule DNA Replication with Fluorescence Microscopy. J Vis Exp. 2009 Oct 09; (32). PMID: 19820685.
    Citations: 3     Fields:    Translation:Cells
  36. Kochaniak AB, Habuchi S, Loparo JJ, Chang DJ, Cimprich KA, Walter JC, van Oijen AM. Proliferating cell nuclear antigen uses two distinct modes to move along DNA. J Biol Chem. 2009 Jun 26; 284(26):17700-10. PMID: 19411704.
    Citations: 62     Fields:    Translation:AnimalsCells
  37. Tanner NA, Loparo JJ, Hamdan SM, Jergic S, Dixon NE, van Oijen AM. Real-time single-molecule observation of rolling-circle DNA replication. Nucleic Acids Res. 2009 Mar; 37(4):e27. PMID: 19155275.
    Citations: 33     Fields:    Translation:Cells
  38. Hamdan SM, Loparo JJ, Takahashi M, Richardson CC, van Oijen AM. Dynamics of DNA replication loops reveal temporal control of lagging-strand synthesis. Nature. 2009 Jan 15; 457(7227):336-9. PMID: 19029884.
    Citations: 76     Fields:    Translation:Cells
  39. Loparo JJ, Roberts ST, Tokmakoff A. Multidimensional infrared spectroscopy of water. II. Hydrogen bond switching dynamics. J Chem Phys. 2006 Nov 21; 125(19):194522. PMID: 17129138.
    Citations: 12     Fields:    
  40. Loparo JJ, Roberts ST, Tokmakoff A. Multidimensional infrared spectroscopy of water. I. Vibrational dynamics in two-dimensional IR line shapes. J Chem Phys. 2006 Nov 21; 125(19):194521. PMID: 17129137.
    Citations: 20     Fields:    
  41. Roberts ST, Loparo JJ, Tokmakoff A. Characterization of spectral diffusion from two-dimensional line shapes. J Chem Phys. 2006 Aug 28; 125(8):084502. PMID: 16965024.
    Citations: 26     Fields:    
  42. Eaves JD, Loparo JJ, Fecko CJ, Roberts ST, Tokmakoff A, Geissler PL. Hydrogen bonds in liquid water are broken only fleetingly. Proc Natl Acad Sci U S A. 2005 Sep 13; 102(37):13019-22. PMID: 16135564.
    Citations: 42     Fields:    Translation:Cells
  43. Fecko CJ, Loparo JJ, Roberts ST, Tokmakoff A. Local hydrogen bonding dynamics and collective reorganization in water: ultrafast infrared spectroscopy of HOD/D(2)O. J Chem Phys. 2005 Feb 01; 122(5):54506. PMID: 15740338.
    Citations: 30     Fields:    
  44. Fecko CJ, Eaves JD, Loparo JJ, Tokmakoff A, Geissler PL. Ultrafast hydrogen-bond dynamics in the infrared spectroscopy of water. Science. 2003 Sep 19; 301(5640):1698-702. PMID: 14500975.
    Citations: 85     Fields:    
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Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.