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Sreenivas Kanugula
Title Assistant Professor
Institution College of Medicine
Department Cellular and Molecular Physiology
Address 500 University Drive Hershey PA 17033
Mailbox: H166
Telephone 7175316987
Email
Background
PREFERRED TITLE/ROLE:

Assistant Professor of Cellular and Molecular Physiology

EDUCATION:

Ph.D., University of Hyderabad, 1995;
Postdoctoral Training, Penn State College of Medicine, 1994-1997

NARRATIVE:

AGT protein removes alkyl adducts from O6 -position of guanine and O4-position of thymine in DNA and protects living organisms from mutagenic and carcinogenic (DNA alkylating) agents. Despite the protective role of the AGT protein in maintaining the integrity of DNA in a cell, the presence of AGT protein is responsible for resistance of tumor cells to alkylating chemotherapeutic agents. The current research aims at studying the biochemical and functional properties of AGT proteins from different species. This study would help us in designing inhibitors for human AGT protein, as inactivation of this DNA repair function enhances the efficacy of the alkylating agents used in cancer chemotherapy.
Publications
1. Kotandeniya D, Murphy D, Seneviratne U, Guza R, Pegg A, Kanugula S, Tretyakova N. Mass spectrometry based approach to study the kinetics of O6-alkylguanine DNA alkyltransferase-mediated repair of O6-pyridyloxobutyl-2'-deoxyguanosine adducts in DNA. Chem Res Toxicol. 2011 Nov 21; 24(11):1966-75.
  View in: PubMed
 
2. Green R, Hanfrey CC, Elliott KA, McCloskey DE, Wang X, Kanugula S, Pegg AE, Michael AJ. Independent evolutionary origins of functional polyamine biosynthetic enzyme fusions catalysing de novo diamine to triamine formation. Mol Microbiol. 2011 Aug; 81(4):1109-24.
  View in: PubMed
 
3. Aramini JM, Tubbs JL, Kanugula S, Rossi P, Ertekin A, Maglaqui M, Hamilton K, Ciccosanti CT, Jiang M, Xiao R, Soong TT, Rost B, Acton TB, Everett JK, Pegg AE, Tainer JA, Montelione GT. Structural basis of O6-alkylguanine recognition by a bacterial alkyltransferase-like DNA repair protein. J Biol Chem. 2010 Apr 30; 285(18):13736-41.
  View in: PubMed
 
4. Fang Q, Kanugula S, Tubbs JL, Tainer JA, Pegg AE. Repair of O4-alkylthymine by O6-alkylguanine-DNA alkyltransferases. J Biol Chem. 2010 Mar 12; 285(11):8185-95.
  View in: PubMed
 
5. Tubbs JL, Latypov V, Kanugula S, Butt A, Melikishvili M, Kraehenbuehl R, Fleck O, Marriott A, Watson AJ, Verbeek B, McGown G, Thorncroft M, Santibanez-Koref MF, Millington C, Arvai AS, Kroeger MD, Peterson LA, Williams DM, Fried MG, Margison GP, Pegg AE, Tainer JA. Flipping of alkylated DNA damage bridges base and nucleotide excision repair. Nature. 2009 Jun 11; 459(7248):808-13.
  View in: PubMed
 
6. Philip S, Swaminathan S, Kuznetsov SG, Kanugula S, Biswas K, Chang S, Loktionova NA, Haines DC, Kaldis P, Pegg AE, Sharan SK. Degradation of BRCA2 in alkyltransferase-mediated DNA repair and its clinical implications. Cancer Res. 2008 Dec 1; 68(23):9973-81.
  View in: PubMed
 
7. Mijal RS, Kanugula S, Vu CC, Fang Q, Pegg AE, Peterson LA. DNA sequence context affects repair of the tobacco-specific adduct O(6)-[4-Oxo-4-(3-pyridyl)butyl]guanine by human O(6)-alkylguanine-DNA alkyltransferases. Cancer Res. 2006 May 1; 66(9):4968-74.
  View in: PubMed
 
8. Fang Q, Kanugula S, Pegg AE. Function of domains of human O6-alkylguanine-DNA alkyltransferase. Biochemistry. 2005 Nov 22; 44(46):15396-405.
  View in: PubMed
 
9. Kanugula S, Pauly GT, Moschel RC, Pegg AE. A bifunctional DNA repair protein from Ferroplasma acidarmanus exhibits O6-alkylguanine-DNA alkyltransferase and endonuclease V activities. Proc Natl Acad Sci U S A. 2005 Mar 8; 102(10):3617-22.
  View in: PubMed
 
10. Ackermann JM, Kanugula S, Pegg AE. DNAzyme-mediated silencing of ornithine decarboxylase. Biochemistry. 2005 Feb 15; 44(6):2143-52.
  View in: PubMed
 
11. Mijal RS, Thomson NM, Fleischer NL, Pauly GT, Moschel RC, Kanugula S, Fang Q, Pegg AE, Peterson LA. The repair of the tobacco specific nitrosamine derived adduct O6-[4-Oxo-4-(3-pyridyl)butyl]guanine by O6-alkylguanine-DNA alkyltransferase variants. Chem Res Toxicol. 2004 Mar; 17(3):424-34.
  View in: PubMed
 
12. Liu L, Hachey DL, Valadez G, Williams KM, Guengerich FP, Loktionova NA, Kanugula S, Pegg AE. Characterization of a mutagenic DNA adduct formed from 1,2-dibromoethane by O6-alkylguanine-DNA alkyltransferase. J Biol Chem. 2004 Feb 6; 279(6):4250-9.
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13. Kanugula S, Pegg AE. Alkylation damage repair protein O6-alkylguanine-DNA alkyltransferase from the hyperthermophiles Aquifex aeolicus and Archaeoglobus fulgidus. Biochem J. 2003 Oct 15; 375(Pt 2):449-55.
  View in: PubMed
 
14. Rasimas JJ, Kanugula S, Dalessio PM, Ropson IJ, Fried MG, Pegg AE. Effects of zinc occupancy on human O6-alkylguanine-DNA alkyltransferase. Biochemistry. 2003 Feb 4; 42(4):980-90.
  View in: PubMed
 
15. Luu KX, Kanugula S, Pegg AE, Pauly GT, Moschel RC. Repair of oligodeoxyribonucleotides by O(6)-alkylguanine-DNA alkyltransferase. Biochemistry. 2002 Jul 9; 41(27):8689-97.
  View in: PubMed
 
16. Liu L, Xu-Welliver M, Kanugula S, Pegg AE. Inactivation and degradation of O(6)-alkylguanine-DNA alkyltransferase after reaction with nitric oxide. Cancer Res. 2002 Jun 1; 62(11):3037-43.
  View in: PubMed
 
17. Pegg AE, Goodtzova K, Loktionova NA, Kanugula S, Pauly GT, Moschel RC. Inactivation of human O(6)-alkylguanine-DNA alkyltransferase by modified oligodeoxyribonucleotides containing O(6)-benzylguanine. J Pharmacol Exp Ther. 2001 Mar; 296(3):958-65.
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18. Kanugula S, Pegg AE. Novel DNA repair alkyltransferase from Caenorhabditis elegans. Environ Mol Mutagen. 2001; 38(2-3):235-43.
  View in: PubMed
 
19. Griffin RJ, Arris CE, Bleasdale C, Boyle FT, Calvert AH, Curtin NJ, Dalby C, Kanugula S, Lembicz NK, Newell DR, Pegg AE, Golding BT. Resistance-modifying agents. 8. Inhibition of O(6)-alkylguanine-DNA alkyltransferase by O(6)-alkenyl-, O(6)-cycloalkenyl-, and O(6)-(2-oxoalkyl)guanines and potentiation of temozolomide cytotoxicity in vitro by O(6)-(1-cyclopentenylmethyl)guanine. J Med Chem. 2000 Nov 2; 43(22):4071-83.
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20. Xu-Welliver M, Kanugula S, Loktionova NA, Crone TM, Pegg AE. Conserved residue lysine165 is essential for the ability of O6-alkylguanine-DNA alkyltransferase to react with O6-benzylguanine. Biochem J. 2000 Apr 15; 347(Pt 2):527-34.
  View in: PubMed
 
21. Daniels DS, Mol CD, Arvai AS, Kanugula S, Pegg AE, Tainer JA. Active and alkylated human AGT structures: a novel zinc site, inhibitor and extrahelical base binding. EMBO J. 2000 Apr 3; 19(7):1719-30.
  View in: PubMed
 
22. Xu-Welliver M, Leitão J, Kanugula S, Meehan WJ, Pegg AE. Role of codon 160 in the sensitivity of human O6-alkylguanine-DNA alkyltransferase to O6-benzylguanine. Biochem Pharmacol. 1999 Oct 15; 58(8):1279-85.
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23. Loktionova NA, Xu-Welliver M, Crone TM, Kanugula S, Pegg AE. Protection of CHO cells by mutant forms of O6-alkylguanine-DNA alkyltransferase from killing by 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) plus O6-benzylguanine or O6-benzyl-8-oxoguanine. Biochem Pharmacol. 1999 Jul 15; 58(2):237-44.
  View in: PubMed
 
24. Spratt TE, Wu JD, Levy DE, Kanugula S, Pegg AE. Reaction and binding of oligodeoxynucleotides containing analogues of O6-methylguanine with wild-type and mutant human O6-alkylguanine-DNA alkyltransferase. Biochemistry. 1999 May 25; 38(21):6801-6.
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25. Xu-Welliver M, Leitão J, Kanugula S, Pegg AE. Alteration of the conserved residue tyrosine-158 to histidine renders human O6-alkylguanine-DNA alkyltransferase insensitive to the inhibitor O6-benzylguanine. Cancer Res. 1999 Apr 1; 59(7):1514-9.
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26. Edara S, Kanugula S, Pegg AE. Expression of the inactive C145A mutant human O6-alkylguanine-DNA alkyltransferase in E.coli increases cell killing and mutations by N-methyl-N'-nitro-N-nitrosoguanidine. Carcinogenesis. 1999 Jan; 20(1):103-8.
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27. Goodtzova K, Kanugula S, Edara S, Pegg AE. Investigation of the role of tyrosine-114 in the activity of human O6-alkylguanine-DNA alkyltranferase. Biochemistry. 1998 Sep 8; 37(36):12489-95.
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28. Pegg AE, Kanugula S, Edara S, Pauly GT, Moschel RC, Goodtzova K. Reaction of O6-benzylguanine-resistant mutants of human O6-alkylguanine-DNA alkyltransferase with O6-benzylguanine in oligodeoxyribonucleotides. J Biol Chem. 1998 May 1; 273(18):10863-7.
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29. Xu-Welliver M, Kanugula S, Pegg AE. Isolation of human O6-alkylguanine-DNA alkyltransferase mutants highly resistant to inactivation by O6-benzylguanine. Cancer Res. 1998 May 1; 58(9):1936-45.
  View in: PubMed
 
30. Kanugula S, Goodtzova K, Pegg AE. Probing of conformational changes in human O6-alkylguanine-DNA alkyl transferase protein in its alkylated and DNA-bound states by limited proteolysis. Biochem J. 1998 Feb 1; 329 ( Pt 3):545-50.
  View in: PubMed
 
31. Goodtzova K, Kanugula S, Edara S, Pauly GT, Moschel RC, Pegg AE. Repair of O6-benzylguanine by the Escherichia coli Ada and Ogt and the human O6-alkylguanine-DNA alkyltransferases. J Biol Chem. 1997 Mar 28; 272(13):8332-9.
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32. Edara S, Kanugula S, Goodtzova K, Pegg AE. Resistance of the human O6-alkylguanine-DNA alkyltransferase containing arginine at codon 160 to inactivation by O6-benzylguanine. Cancer Res. 1996 Dec 15; 56(24):5571-5.
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33. Fried MG, Kanugula S, Bromberg JL, Pegg AE. DNA binding mechanism of O6-alkylguanine-DNA alkyltransferase: stoichiometry and effects of DNA base composition and secondary structure on complex stability. Biochemistry. 1996 Dec 3; 35(48):15295-301.
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34. Crone TM, Kanugula S, Pegg AE. Mutations in the Ada O6-alkylguanine-DNA alkyltransferase conferring sensitivity to inactivation by O6-benzylguanine and 2,4-diamino-6-benzyloxy-5-nitrosopyrimidine. Carcinogenesis. 1995 Aug; 16(8):1687-92.
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35. Kanugula S, Goodtzova K, Edara S, Pegg AE. Alteration of arginine-128 to alanine abolishes the ability of human O6-alkylguanine-DNA alkyltransferase to repair methylated DNA but has no effect on its reaction with O6-benzylguanine. Biochemistry. 1995 May 30; 34(21):7113-9.
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36. Chae MY, Swenn K, Kanugula S, Dolan ME, Pegg AE, Moschel RC. 8-Substituted O6-benzylguanine, substituted 6(4)-(benzyloxy)pyrimidine, and related derivatives as inactivators of human O6-alkylguanine-DNA alkyltransferase. J Med Chem. 1995 Jan 20; 38(2):359-65.
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Co-Authors  
Dalessio, Paula
Loktionova, Natalia
Mccloskey, Diane
Pegg, Anthony
Spratt, Thomas
See all (6) people
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