Trypanosome Prereplication Machinery: a Potential New Target for an Old Problem

Overview

Journal Enzyme Res

Publisher Hindawi

Date 2011 Jul 15

PMID 21755041

Citations 4

Authors

Simone Guedes Calderano

Patricia Diogo de Melo Godoy

Julia Pinheiro Chagas da Cunha

Maria Carolina Elias

Affiliations

Soon will be listed here.

Abstract

Approximately ten million people suffer from Chagas disease worldwide, caused by Trypanosoma cruzi, with the disease burden predominately focused in Latin America. Sleeping sickness is another serious health problem, caused by Trypanosoma brucei, especially in sub-Saharan countries. Unfortunately, the drugs currently available to treat these diseases have toxic effects and are not effective against all disease phases or parasite strains. Therefore, there is a clear need for the development of novel drugs and drug targets to treat these diseases. We propose the trypanosome prereplication machinery component, Orc1/Cdc6, as a potential target for drug development. In trypanosomes, Orc1/Cdc6 is involved in nuclear DNA replication, and, despite its involvement in such a conserved process, Orc1/Cdc6 is distinct from mammalian Orc1 and Cdc6 proteins. Moreover, RNAi-mediated silencing of trypanosome Orc1/Cdc6 expression in T. brucei decreased cell survival, indicating that Orc1/Cdc6 is critical for trypanosome survival.

Citing Articles

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DNA replication protein Cdc45 directly interacts with PCNA via its PIP box in Leishmania donovani and the Cdc45 PIP box is essential for cell survival.

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References

Apt W . Current and developing therapeutic agents in the treatment of Chagas disease. Drug Des Devel Ther. 2010; 4:243-53. PMC: 2948934. DOI: 10.2147/dddt.s8338. View

Magnus E, Vervoort T, VAN MEIRVENNE N . A card-agglutination test with stained trypanosomes (C.A.T.T.) for the serological diagnosis of T. B. gambiense trypanosomiasis. Ann Soc Belg Med Trop. 1978; 58(3):169-76. View

Bell S, Stillman B . ATP-dependent recognition of eukaryotic origins of DNA replication by a multiprotein complex. Nature. 1992; 357(6374):128-34. DOI: 10.1038/357128a0. View

DUGGAN A, HUTCHINSON M . Sleeping sickness in Europeans: a review of 109 cases. J Trop Med Hyg. 1966; 69(6):124-31. View

Russomando G, de Tomassone M, De Guillen I, Acosta N, Vera N, Almiron M . Treatment of congenital Chagas' disease diagnosed and followed up by the polymerase chain reaction. Am J Trop Med Hyg. 1998; 59(3):487-91. DOI: 10.4269/ajtmh.1998.59.487. View

Duncker B, Chesnokov I, McConkey B . The origin recognition complex protein family. Genome Biol. 2009; 10(3):214. PMC: 2690993. DOI: 10.1186/gb-2009-10-3-214. View

Pratt W, Morishima Y, Osawa Y . The Hsp90 chaperone machinery regulates signaling by modulating ligand binding clefts. J Biol Chem. 2008; 283(34):22885-9. PMC: 2516982. DOI: 10.1074/jbc.R800023200. View

Hartwell L . Sequential function of gene products relative to DNA synthesis in the yeast cell cycle. J Mol Biol. 1976; 104(4):803-17. DOI: 10.1016/0022-2836(76)90183-2. View

Whitesell L, Lindquist S . HSP90 and the chaperoning of cancer. Nat Rev Cancer. 2005; 5(10):761-72. DOI: 10.1038/nrc1716. View

10.

Scholefield G, Veening J, Murray H . DnaA and ORC: more than DNA replication initiators. Trends Cell Biol. 2010; 21(3):188-94. DOI: 10.1016/j.tcb.2010.10.006. View

11.

Sexton J, Wigle T, He Q, Hughes M, Smith G, Singleton S . Novel Inhibitors of E. coli RecA ATPase Activity. Curr Chem Genomics. 2010; 4:34-42. PMC: 2905775. DOI: 10.2174/1875397301004010034. View

12.

Leguizamon M, Russomando G, Luquetti A, Rassi A, Almiron M, Frasch A . Long-lasting antibodies detected by a trans-sialidase inhibition assay of sera from parasite-free, serologically cured chagasic patients. J Infect Dis. 1997; 175(5):1272-5. DOI: 10.1086/593697. View

13.

Miller P, Schnur R, Barbacci E, Moyer M, Moyer J . Binding of benzoquinoid ansamycins to p100 correlates with their ability to deplete the erbB2 gene product p185. Biochem Biophys Res Commun. 1994; 201(3):1313-9. DOI: 10.1006/bbrc.1994.1847. View

14.

Neuwald A, Aravind L, Spouge J, Koonin E . AAA+: A class of chaperone-like ATPases associated with the assembly, operation, and disassembly of protein complexes. Genome Res. 1999; 9(1):27-43. View

15.

Ostrov D, Hernandez Prada J, Corsino P, Finton K, Le N, Rowe T . Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening. Antimicrob Agents Chemother. 2007; 51(10):3688-98. PMC: 2043263. DOI: 10.1128/AAC.00392-07. View

16.

Walker J, Saraste M, Runswick M, Gay N . Distantly related sequences in the alpha- and beta-subunits of ATP synthase, myosin, kinases and other ATP-requiring enzymes and a common nucleotide binding fold. EMBO J. 1982; 1(8):945-51. PMC: 553140. DOI: 10.1002/j.1460-2075.1982.tb01276.x. View

17.

Odiit M, Kansiime F, Enyaru J . Duration of symptoms and case fatality of sleeping sickness caused by Trypanosoma brucei rhodesiense in Tororo, Uganda. East Afr Med J. 1998; 74(12):792-5. View

18.

Randell J, Bowers J, Rodriguez H, Bell S . Sequential ATP hydrolysis by Cdc6 and ORC directs loading of the Mcm2-7 helicase. Mol Cell. 2006; 21(1):29-39. DOI: 10.1016/j.molcel.2005.11.023. View

19.

Evrin C, Clarke P, Zech J, Lurz R, Sun J, Uhle S . A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. Proc Natl Acad Sci U S A. 2009; 106(48):20240-5. PMC: 2787165. DOI: 10.1073/pnas.0911500106. View

20.

Burri C, Brun R . Eflornithine for the treatment of human African trypanosomiasis. Parasitol Res. 2003; 90 Supp 1:S49-52. DOI: 10.1007/s00436-002-0766-5. View