Profile

On-going efforts in my laboratory focus on the following areas. (i) Structure/function analyses of native and chemically modified nucleic acids and etiology of nucleic acid structure. Using chemical synthesis and structure determination at high resolution, the effects of chemical modifications on the structures of DNA and RNA are examined and the results correlated with stability and in vitro and in vivo activity data to direct the design of nucleic acid analogs with improved efficacies for antisense and RNAi applications. We are collaborating with researchers from Alnylam Pharmaceuticals Inc. (Cambridge, MA) and Isis Pharmaceuticals Inc. (Carlsbad, CA) to exploit insights from structural studies for the design of next generation antisense and siRNA therapeutics. (ii) Chemistry and biology of carcinogen-DNA adducts. This program examines relationships between the structure and biological processing of damaged bases by Y-class trans-lesion DNA polymerases (i.e. Dpo4 from Sulfolobus solfataricus and human Pol-iota, Pol-kappa and Pol-eta). Using in vitro primer extension assays in combination with steady state and pre-steady state kinetics as well as mass spectrometry, we are probing the effects on the accuracy of replication of a range of adducts inside the template strand (8-oxo-dG, O6-methyl-dG, N2-methyl-dG, 1,N2-etheno-dG, acrolein, cyclic pyrimidine dimers and others). Crystal structures of binary Pol-DNA and ternary Pol-DNA-dNTP complexes are determined to shed light on the consequences of individual lesions for the accuracy of bypass. (iii) The cyanobacterial KaiABC circadian clock. The circadian clock of Synechococcus elongatus can be reconstituted in vitro with the three proteins KaiA, KaiB and KaiC in the presence of ATP and Mg2+. KaiC is the central cog and exhibits kinase, phosphatase and ATPase activities, KaiA enhances KaiC phosphorylation and KaiB antagonizes KaiA. Remarkably, this post-translational timer exhibits all the hallmarks of circadian clocks - a period of ca. 24 hours, entrainment and temperature compensation - thus permitting its dissection by biochemical and biophysical means. Using a hybrid structural approach including single crystal X-ray crystallography, electron microscopy and small angle X-ray and neutron scattering in combination with functional studies in vitro and in vivo, we are analyzing the protein-protein interactions and mechanistic aspects of this molecular clock.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Intricate protein-protein interactions in the cyanobacterial circadian clock. Egli M (2014) J Biol Chem 289(31): 21267-75
    › Primary publication · 24936066 (PubMed) · PMC4118088 (PubMed Central)
  2. Metabolic compensation and circadian resilience in prokaryotic cyanobacteria. Johnson CH, Egli M (2014) Annu Rev Biochem : 221-47
    › Primary publication · 24905782 (PubMed) · PMC4259047 (PubMed Central)
  3. An arginine tetrad as mediator of input-dependent and input-independent ATPases in the clock protein KaiC. Pattanayek R, Xu Y, Lamichhane A, Johnson CH, Egli M (2014) Acta Crystallogr D Biol Crystallogr 70(Pt 5): 1375-90
    › Primary publication · 24816106 (PubMed) · PMC4722857 (PubMed Central)
  4. Amides are excellent mimics of phosphate internucleoside linkages and are well tolerated in short interfering RNAs. Mutisya D, Selvam C, Lunstad BD, Pallan PS, Haas A, Leake D, Egli M, Rozners E (2014) Nucleic Acids Res 42(10): 6542-51
    › Primary publication · 24813446 (PubMed) · PMC4041415 (PubMed Central)
  5. Kinetics, structure, and mechanism of 8-Oxo-7,8-dihydro-2'-deoxyguanosine bypass by human DNA polymerase η. Patra A, Nagy LD, Zhang Q, Su Y, Müller L, Guengerich FP, Egli M (2014) J Biol Chem 289(24): 16867-82
    › Primary publication · 24759104 (PubMed) · PMC4059130 (PubMed Central)
  6. 2'-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity. Wu SY, Yang X, Gharpure KM, Hatakeyama H, Egli M, McGuire MH, Nagaraja AS, Miyake TM, Rupaimoole R, Pecot CV, Taylor M, Pradeep S, Sierant M, Rodriguez-Aguayo C, Choi HJ, Previs RA, Armaiz-Pena GN, Huang L, Martinez C, Hassell T, Ivan C, Sehgal V, Singhania R, Han HD, Su C, Kim JH, Dalton HJ, Kovvali C, Keyomarsi K, McMillan NA, Overwijk WW, Liu J, Lee JS, Baggerly KA, Lopez-Berestein G, Ram PT, Nawrot B, Sood AK (2014) Nat Commun : 3459
    › Primary publication · 24619206 (PubMed) · PMC4112501 (PubMed Central)
  7. Leukotriene biosynthesis inhibitor MK886 impedes DNA polymerase activity. Ketkar A, Zafar MK, Maddukuri L, Yamanaka K, Banerjee S, Egli M, Choi JY, Lloyd RS, Eoff RL (2013) Chem Res Toxicol 26(2): 221-32
    › Primary publication · 23305233 (PubMed) · PMC3578163 (PubMed Central)
  8. Synthesis, duplex stabilization and structural properties of a fluorinated carbocyclic LNA analogue. Seth PP, Pallan PS, Swayze EE, Egli M (2013) Chembiochem 14(1): 58-62
    › Primary publication · 23193103 (PubMed) · PMC3684079 (PubMed Central)
  9. A comprehensive strategy to discover inhibitors of the translesion synthesis DNA polymerase κ. Yamanaka K, Dorjsuren D, Eoff RL, Egli M, Maloney DJ, Jadhav A, Simeonov A, Lloyd RS (2012) PLoS One 7(10): e45032
    › Primary publication · 23056190 (PubMed) · PMC3466269 (PubMed Central)
  10. Differential furanose selection in the active sites of archaeal DNA polymerases probed by fixed-conformation nucleotide analogues. Ketkar A, Zafar MK, Banerjee S, Marquez VE, Egli M, Eoff RL (2012) Biochemistry 51(45): 9234-44
    › Primary publication · 23050956 (PubMed) · PMC3563936 (PubMed Central)
  11. A nucleotide-analogue-induced gain of function corrects the error-prone nature of human DNA polymerase iota. Ketkar A, Zafar MK, Banerjee S, Marquez VE, Egli M, Eoff RL (2012) J Am Chem Soc 134(25): 10698-705
    › Primary publication · 22632140 (PubMed) · PMC3392044 (PubMed Central)
  12. Structure and nuclease resistance of 2',4'-constrained 2'-O-methoxyethyl (cMOE) and 2'-O-ethyl (cEt) modified DNAs. Pallan PS, Allerson CR, Berdeja A, Seth PP, Swayze EE, Prakash TP, Egli M (2012) Chem Commun (Camb) 48(66): 8195-7
    › Primary publication · 22614180 (PubMed) · PMC3404228 (PubMed Central)
  13. Synthesis and antisense properties of fluoro cyclohexenyl nucleic acid (F-CeNA), a nuclease stable mimic of 2'-fluoro RNA. Seth PP, Yu J, Jazayeri A, Pallan PS, Allerson CR, Østergaard ME, Liu F, Herdewijn P, Egli M, Swayze EE (2012) J Org Chem 77(11): 5074-85
    › Primary publication · 22591005 (PubMed) · PMC3696582 (PubMed Central)
  14. The steric hypothesis for DNA replication and fluorine hydrogen bonding revisited in light of structural data. Egli M (2012) Acc Chem Res 45(8): 1237-46
    › Primary publication · 22524491 (PubMed) · PMC3419310 (PubMed Central)
  15. Replication of N2,3-ethenoguanine by DNA polymerases. Zhao L, Christov PP, Kozekov ID, Pence MG, Pallan PS, Rizzo CJ, Egli M, Guengerich FP (2012) Angew Chem Int Ed Engl 51(22): 5466-9
    › Primary publication · 22488769 (PubMed) · PMC3671877 (PubMed Central)
  16. The conformationally constrained N-methanocarba-dT analogue adopts an unexpected C4'-exo sugar pucker in the structure of a DNA hairpin. Pallan PS, Marquez VE, Egli M (2012) Biochemistry 51(13): 2639-41
    › Primary publication · 22409313 (PubMed) · PMC3330753 (PubMed Central)
  17. Structures of KaiC circadian clock mutant proteins: a new phosphorylation site at T426 and mechanisms of kinase, ATPase and phosphatase. Pattanayek R, Mori T, Xu Y, Pattanayek S, Johnson CH, Egli M (2009) PLoS One 4(11): e7529
    › Primary publication · 19956664 (PubMed) · PMC2777353 (PubMed Central)
  18. Intramolecular regulation of phosphorylation status of the circadian clock protein KaiC. Xu Y, Mori T, Qin X, Yan H, Egli M, Johnson CH (2009) PLoS One 4(11): e7509
    › Primary publication · 19946629 (PubMed) · PMC2778140 (PubMed Central)
  19. Interplay of structure, hydration and thermal stability in formacetal modified oligonucleotides: RNA may tolerate nonionic modifications better than DNA. Kolarovic A, Schweizer E, Greene E, Gironda M, Pallan PS, Egli M, Rozners E (2009) J Am Chem Soc 131(41): 14932-7
    › Primary publication · 19824732 (PubMed) · PMC2823299 (PubMed Central)
  20. Pairing geometry of the hydrophobic thymine analogue 2,4-difluorotoluene in duplex DNA as analyzed by X-ray crystallography. Pallan PS, Egli M (2009) J Am Chem Soc 131(35): 12548-9
    › Primary publication · 19685868 (PubMed) · PMC2757930 (PubMed Central)
  21. Structure-function relationships in miscoding by Sulfolobus solfataricus DNA polymerase Dpo4: guanine N2,N2-dimethyl substitution produces inactive and miscoding polymerase complexes. Zhang H, Eoff RL, Kozekov ID, Rizzo CJ, Egli M, Guengerich FP (2009) J Biol Chem 284(26): 17687-99
    › Primary publication · 19542237 (PubMed) · PMC2719408 (PubMed Central)
  22. Structural and functional elucidation of the mechanism promoting error-prone synthesis by human DNA polymerase kappa opposite the 7,8-dihydro-8-oxo-2'-deoxyguanosine adduct. Irimia A, Eoff RL, Guengerich FP, Egli M (2009) J Biol Chem 284(33): 22467-80
    › Primary publication · 19542228 (PubMed) · PMC2755968 (PubMed Central)
  23. Structural and functional analysis of Sulfolobus solfataricus Y-family DNA polymerase Dpo4-catalyzed bypass of the malondialdehyde-deoxyguanosine adduct. Eoff RL, Stafford JB, Szekely J, Rizzo CJ, Egli M, Guengerich FP, Marnett LJ (2009) Biochemistry 48(30): 7079-88
    › Primary publication · 19492857 (PubMed) · PMC2717710 (PubMed Central)
  24. Structural insights into a circadian oscillator. Johnson CH, Egli M, Stewart PL (2008) Science 322(5902): 697-701
    › Primary publication · 18974343 (PubMed) · PMC2588432 (PubMed Central)
  25. Effects of N2,N2-dimethylguanosine on RNA structure and stability: crystal structure of an RNA duplex with tandem m2 2G:A pairs. Pallan PS, Kreutz C, Bosio S, Micura R, Egli M (2008) RNA 14(10): 2125-35
    › Primary publication · 18772248 (PubMed) · PMC2553729 (PubMed Central)
  26. Insights into RNA/DNA hybrid recognition and processing by RNase H from the crystal structure of a non-specific enzyme-dsDNA complex. Pallan PS, Egli M (2008) Cell Cycle 7(16): 2562-9
    › Primary publication · 18719385 (PubMed) · PMC3689302 (PubMed Central)
  27. 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] modified oligonucleotides: symbiosis of charge interaction factors and stereoelectronic effects. Prhavc M, Prakash TP, Minasov G, Cook PD, Egli M, Manoharan M (2003) Org Lett 5(12): 2017-20
    › Primary publication · 12790517 (PubMed)
  28. 2'-O-[2-(methylthio)ethyl]-modified oligonucleotide: an analogue of 2'-O-[2-(methoxy)-ethyl]-modified oligonucleotide with improved protein binding properties and high binding affinity to target RNA. Prakash TP, Manoharan M, Kawasaki AM, Fraser AS, Lesnik EA, Sioufi N, Leeds JM, Teplova M, Egli M (2002) Biochemistry 41(39): 11642-8
    › Primary publication · 12269806 (PubMed)
  29. Internal derivatization of oligonucleotides with selenium for X-ray crystallography using MAD. Du Q, Carrasco N, Teplova M, Wilds CJ, Egli M, Huang Z (2002) J Am Chem Soc 124(1): 24-5
    › Primary publication · 11772055 (PubMed)
  30. Redesigning nucleic acids. Benner SA, Battersby TR, Eschgfaller B, Hutter D, Kodra JT, Lutz S, Arslan T, Baschlin DK, Blattler M, Egli M, Hammer C, Held HA, Horlacher J, Huang Z, Hyrup B, Jenny TF, Jurczyk SC, Konig M, von Krosigk U, Lutz MJ, MacPherson LJ, Moroney SE, Muller E, Nambiar KP, Piccirilli JA, Switzer CY, Vogel JJ, Richert C, Roughton AL, Schmidt J, Schneider KC, Stackhouse J (1998) Pure Appl Chem 70(2): 263-6
    › Primary publication · 11542721 (PubMed)
  31. A protein kinase associated with apoptosis and tumor suppression: structure, activity, and discovery of peptide substrates. Velentza AV, Schumacher AM, Weiss C, Egli M, Watterson DM (2001) J Biol Chem 276(42): 38956-65
    › Primary publication · 11483604 (PubMed)
  32. Crystal structure of an RNA duplex containing phenyl-ribonucleotides, hydrophobic isosteres of the natural pyrimidines. Minasov G, Matulic-Adamic J, Wilds CJ, Haeberli P, Usman N, Beigelman L, Egli M (2000) RNA 6(11): 1516-28
    › Primary publication · 11105752 (PubMed) · PMC1370022 (PubMed Central)
  33. Synthetic oligonucleotides as RNA mimetics: 2'-modified Rnas and N3'-->P5' phosphoramidates. Egli M, Gryaznov SM (2000) Cell Mol Life Sci 57(10): 1440-56
    › Primary publication · 11078022 (PubMed)
  34. Functional implications from crystal structures of the conserved Bacillus subtilis protein Maf with and without dUTP. Minasov G, Teplova M, Stewart GC, Koonin EV, Anderson WF, Egli M (2000) Proc Natl Acad Sci U S A 97(12): 6328-33
    › Primary publication · 10841541 (PubMed) · PMC18602 (PubMed Central)
  35. Crystal structure of a conformation-selective casein kinase-1 inhibitor. Mashhoon N, DeMaggio AJ, Tereshko V, Bergmeier SC, Egli M, Hoekstra MF, Kuret J (2000) J Biol Chem 275(26): 20052-60
    › Primary publication · 10749871 (PubMed)
  36. Structural basis of cleavage by RNase H of hybrids of arabinonucleic acids and RNA. Minasov G, Teplova M, Nielsen P, Wengel J, Egli M (2000) Biochemistry 39(13): 3525-32
    › Primary publication · 10736151 (PubMed)
  37. X-ray crystallographic analysis of the hydration of A- and B-form DNA at atomic resolution. Egli M, Tereshko V, Teplova M, Minasov G, Joachimiak A, Sanishvili R, Weeks CM, Miller R, Maier MA, An H, Dan Cook P, Manoharan M (1998) Biopolymers 48(4): 234-52
    › Primary publication · 10699842 (PubMed)
  38. Structural origins of the exonuclease resistance of a zwitterionic RNA. Teplova M, Wallace ST, Tereshko V, Minasov G, Symons AM, Cook PD, Manoharan M, Egli M (1999) Proc Natl Acad Sci U S A 96(25): 14240-5
    › Primary publication · 10588690 (PubMed) · PMC24421 (PubMed Central)