Unravelling the role of SNM1 in the DNA repair system of Trypanosoma brucei. Issue 4 (21st March 2015)

• Record Type: Journal Article
• Authors: Sullivan, James A.; Tong, Jie Lun; Wong, Martin; Kumar, Ambika; Sarkar, Hajrah; Ali, Sarah; Hussein, Ikran; Zaman, Iqra; Meredith, Emma Louise; Helsby, Nuala A.; Hu, Longqin; Wilkinson, Shane R.
• Is Part Of: Molecular microbiology. Volume 96:Issue 4(2015)
• Page Start: 827
• Page End: 838
• Publication Date: 2015-03-21
• Subjects: Molecular microbiology -- Periodicals; 572.829
• DOI: 10.1111/mmi.12973
• Languages: English
• ISSNs: 0950-382X

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>All living cells are subject to agents that promote DNA damage. A particularly lethal lesion are interstrand cross‐links (ICL), a property exploited by several anti‐cancer chemotherapies. In yeast and humans, an enzyme that plays a key role in repairing such damage are the PSO2/SNM1 nucleases. Here, we report that <italic>T</italic><italic>rypanosoma brucei</italic>, the causative agent of African trypanosomiasis, possesses a <italic>bona fide</italic> member of this family (called TbSNM1) with expression of the parasite enzyme able to suppress the sensitivity yeast <italic>pso2Δ</italic> mutants display towards mechlorethamine, an ICL‐inducing compound. By disrupting the Tb<italic>snm1</italic> gene, we demonstrate that TbSNM1 activity is non‐essential to the medically relevant <italic>T</italic><italic>. brucei</italic> life cycle stage. However, trypanosomes lacking this enzyme are more susceptible to bi‐ and tri‐functional DNA alkylating agents with this phenotype readily complemented by ectopic expression of Tb<italic>snm1</italic>. Genetically modified variants of the null mutant line were subsequently used to establish the anti‐parasitic mechanism of action of nitrobenzylphosphoramide mustard and aziridinyl nitrobenzamide prodrugs, compounds previously shown to possess potent trypanocidal properties while exhibiting limited toxicity to mammalian cells. This established that these agents, following activation by a parasite specific type I nitroreductase, produce metabolites that promote formation of ICLs leading to inhibition of trypanosomal growth.</p> </abstract>