The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites.

The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Research Abstract Details 

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The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Abstract Text:

Lara Bethke,Susan Thomas,Kerone Walker,Ronak Lakhia,Radha Rangarajan,Dyann Wirth,

Although the mechanisms by which malaria parasites develop resistance to drugs are unclear, current knowledge suggests a main mechanism of resistance is the alteration of target enzymes by point mutation. In other organisms, defects in DNA mismatch repair have been linked to increased mutation rates and drug resistance. We have identified an unusual complement of mismatch repair genes in the Plasmodium genome. An initial functional test of two of these genes (PfMSH2-1 and PfMSH2-2) using a dominant mutator assay showed an elevation in mutation frequency with the PfMSH2-2 homolog, indirectly demonstrating a role for this gene in mismatch repair. We successfully disrupted PbMSH2-2 in the Plasmodium berghei laboratory isolate NK65, and showed that this gene is not essential for parasite growth in either the asexual (rodent) or sexual (mosquito) stages of the lifecycle. Although we observed some differences in levels of drug resistance between wild type and mutant parasites, no uniform trend emerged and preliminary evidence does not support a strong link between PbMSH2-2 disruption and dramatically increased drug resistance. We found microsatellite polymorphism in the PbMSH2-2 disrupted parasites in less than 40 life cycles post-transfection, but not in PbMap2K disrupted controls or mosquito-passaged wild type parasites, which suggests a possible role for PbMSH2-2 in preventing microsatellite slippage, similar to MSH2 in other organisms. Our studies suggest that Plasmodium species may have evolved a unique variation on the highly conserved system of DNA repair compared to the mismatch repair systems in other eukaryotes.

The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Publishing Authors By Initials

L Bethke,S Thomas,K Walker,R Lakhia,R Rangarajan,D Wirth,

For similar genetic phenomena: variation (genetics) research abstracts see: genetic phenomena: variation (genetics) research

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The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Molecular and biochemical parasitology

VOLUME: 155

Page Numbers: 18-25

Journal Abbreviation: Mol. Biochem. Parasitol.

ISSN: 0166-6851

DAY: 13

MONTH: 05

YEAR: 2007

The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8006324

The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Keywords Mesh Terms:

KEYWORDS: Variation (Genetics)

MESH TERMS: metabolism

Chemical & Substance for Abstract: The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites. Information

Substance Name: 5-fluoroorotic acid

Registry Number: 703-95-7

Grant and Affiliation Information for The role of DNA mismatch repair in generating genetic diversity and drug resistance in malaria parasites.

AFFILIATION: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, United States. lara.bethke@icr.ac.uk

Country: Netherlands

AGENCY: United States NIGMS

GRANT: R01-GM061351

ACRONYM: GM

MEDLINETA: Mol Biochem Parasitol

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