Overview of DNA Repair in Trypanosoma cruzi, Trypanosoma brucei, and Leishmania major

Abstract

A wide variety of DNA lesions arise due to environmental agents, normal cellular metabolism, or intrinsic weaknesses in the chemical bonds of DNA. Diverse cellular mechanisms have evolved to maintain genome stability, including mechanisms to repair damaged DNA, to avoid the incorporation of modified nucleotides, and to tolerate lesions (translesion synthesis). Studies of the mechanisms related to DNA metabolism in trypanosomatids have been very limited. Together with recent experimental studies, the genome sequencing of Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major, three related pathogens with different life cycles and disease pathology, has revealed interesting features of the DNA repair mechanism in these protozoan parasites, which will be reviewed here.

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

“…S1 and S2 and text in the supplemental material). Our results (also available at http: //www.crc.ulaval.ca/trypdnarepair/) complement previous analy-ses (24,25) and will serve as the backbone for the current review. The relevance of DNA repair to the development of drug resistance and its potential as a drug target are also discussed.…”

“…S1B and C and S7A in the supplemental material). This is the case for the presynapsis proteins MRE11, RAD50, NBS1, and RPA, with the T. brucei MRE11 homolog, TbMRE11, being the best characterized (25). MRE11, a member of the lambda phosphatase family of phosphoesterases, is a conserved protein with an N-terminal nuclease domain that has both 3=-to-5= exonuclease and endonuclease activities (155,156).…”

“…Many homologs of the components of the different DNA repair pathways and recombination enzymes were present, with some noticeable absent proteins, such as RAD52 and some components of the nonhomologous endjoining machinery (23). Recombination, repair, and replication enzymes of T. brucei were revisited (24), and more recently DNA repair enzymes in the tritryps were reviewed, adding experimental evidence pertaining to the repair enzymes and focusing on T. cruzi (25). Since repair and recombination in Leishmania were less emphasized, we discuss this here in greater detail while making connections with recent findings for both Leishmania and other kinetoplastids.…”

Adaptive mechanisms in pathogens: universal aneuploidy in Leishmania

“…In trypanosomatids, doublestrand breaks are repaired by homologous recombination (HR), which is also required for correct chromosome segregation during meiosis [65]. Although Leishmania is capable of having a meiosis-like cycle [46], it is rather unlikely that defects in HR are involved in the generation of aneuploids.…”

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

“…These repeats are known to stimulate Rad51-ssDNA binding and to prevent nonspecific Rad51-dsDNA binding (47). Trypanosoma cruzi, T. brucei, and Leishmania major also have BRCA2 homologs with various numbers of BRC repeats (48). Other BRCA2 regions (the oligonucleotide-binding [OB] fold that binds ssDNA and the Tower domain, which binds dsDNA), however, have not been identified in these homologs.…”