K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair
Southeast Asia has been the hotbed for the development of drug-resistant malaria parasites, including those with resistance to artemisinin combination therapy. While mutations in the kelch propeller domain (K13 mutations) are associated with artemisinin resistance, a range of evidence suggests that...
| Main Authors: | , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Online Access: | https://hdl.handle.net/10356/146590 |
| _version_ | 1826111494546259968 |
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| author | Xiong, Aoli Prakash, Prem Gao, Xiaohong Chew, Marvin Tay, Ian Jun Jie Woodrow, Charles J. Engelward, Bevin P. Han, Jongyoon Preiser, Peter Rainer |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Xiong, Aoli Prakash, Prem Gao, Xiaohong Chew, Marvin Tay, Ian Jun Jie Woodrow, Charles J. Engelward, Bevin P. Han, Jongyoon Preiser, Peter Rainer |
| author_sort | Xiong, Aoli |
| collection | NTU |
| description | Southeast Asia has been the hotbed for the development of drug-resistant malaria parasites, including those with resistance to artemisinin combination therapy. While mutations in the kelch propeller domain (K13 mutations) are associated with artemisinin resistance, a range of evidence suggests that other factors are critical for the establishment and subsequent transmission of resistance in the field. Here, we perform a quantitative analysis of DNA damage and repair in the malaria parasite Plasmodium falciparum and find a strong link between enhanced DNA damage repair and artemisinin resistance. This experimental observation is further supported when variations in seven known DNA repair genes are found in resistant parasites, with six of these mutations being associated with K13 mutations. Our data provide important insights on confounding factors that are important for the establishment and spread of artemisinin resistance and may explain why resistance has not yet arisen in Africa. |
| first_indexed | 2024-10-01T02:51:39Z |
| format | Journal Article |
| id | ntu-10356/146590 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:51:39Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1465902023-02-28T17:09:34Z K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair Xiong, Aoli Prakash, Prem Gao, Xiaohong Chew, Marvin Tay, Ian Jun Jie Woodrow, Charles J. Engelward, Bevin P. Han, Jongyoon Preiser, Peter Rainer School of Biological Sciences Science::Biological sciences Artemisinin K13 Protein Southeast Asia has been the hotbed for the development of drug-resistant malaria parasites, including those with resistance to artemisinin combination therapy. While mutations in the kelch propeller domain (K13 mutations) are associated with artemisinin resistance, a range of evidence suggests that other factors are critical for the establishment and subsequent transmission of resistance in the field. Here, we perform a quantitative analysis of DNA damage and repair in the malaria parasite Plasmodium falciparum and find a strong link between enhanced DNA damage repair and artemisinin resistance. This experimental observation is further supported when variations in seven known DNA repair genes are found in resistant parasites, with six of these mutations being associated with K13 mutations. Our data provide important insights on confounding factors that are important for the establishment and spread of artemisinin resistance and may explain why resistance has not yet arisen in Africa. National Research Foundation (NRF) Singapore-MIT Alliance for Research and Technology (SMART) Published version We would like to thank David Fidock (Columbia University, New York, NY, USA) for the P. falciparum Dd2 and Dd2I543T strains. This work was supported by the National Research Foundation, Prime Minister’s Office , Singapore, through the Singapore-MIT Alliance for Research and Technology (SMART) BioSystems and Micromechanics (BioSym) Interdisciplinary Research Group (IRG) (to A.X. and J.H.) and Antimicrobial Resistance IRG (to A.X., J.H., M.Z., W.C., and P.R.P.); and by the Bill and Melinda Gates Foundation (Global Health grant number OPP1040463 to A.X., C.W., P.P., G.X., and P.R.P.). 2021-03-02T05:51:32Z 2021-03-02T05:51:32Z 2020 Journal Article Xiong, A., Prakash, P., Gao, X., Chew, M., Tay, I. J. J., Woodrow, C. J., . . . Preiser, P. R. (2020). K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair. Cell Reports, 32(5), 107996-. doi:10.1016/j.celrep.2020.107996 2211-1247 https://hdl.handle.net/10356/146590 10.1016/j.celrep.2020.107996 32755588 2-s2.0-85088856605 5 32 en Cell Reports © 2020 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). application/pdf |
| spellingShingle | Science::Biological sciences Artemisinin K13 Protein Xiong, Aoli Prakash, Prem Gao, Xiaohong Chew, Marvin Tay, Ian Jun Jie Woodrow, Charles J. Engelward, Bevin P. Han, Jongyoon Preiser, Peter Rainer K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair |
| title | K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair |
| title_full | K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair |
| title_fullStr | K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair |
| title_full_unstemmed | K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair |
| title_short | K13-mediated reduced susceptibility to artemisinin in Plasmodium falciparum is overlaid on a trait of enhanced DNA damage repair |
| title_sort | k13 mediated reduced susceptibility to artemisinin in plasmodium falciparum is overlaid on a trait of enhanced dna damage repair |
| topic | Science::Biological sciences Artemisinin K13 Protein |
| url | https://hdl.handle.net/10356/146590 |
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