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

SUMMARY

All living organisms are continuously faced with endogenous or exogenous stress conditions affecting genome stability. DNA repair pathways act as a defense mechanism, which is essential to maintain DNA integrity. There is much to learn about the regulation and functions of these mechanisms, not only in human cells but also equally in divergent organisms. In trypanosomatids, DNA repair pathways protect the genome against mutations but also act as an adaptive mechanism to promote drug resistance. In this review, we scrutinize the molecular mechanisms and DNA repair pathways which are conserved in trypanosomatids. The recent advances made by the genome consortiums reveal the complete genomic sequences of several pathogens. Therefore, using bioinformatics and genomic sequences, we analyze the conservation of DNA repair proteins and their key protein motifs in trypanosomatids. We thus present a comprehensive view of DNA repair processes in trypanosomatids at the crossroads of DNA repair and drug resistance.     

Mitochondrial DNA Repair Pathways

It has long been held that there is no DNA repair in mitochondria. Early observations suggestedthat the reason for the observed accumulation of DNA damage in mitochondrial DNA is thatDNA lesions are not removed. This is in contrast to the very efficient repair that is seen inthe nuclear DNA. Mitochondrial DNA does not code for any DNA repair proteins, but it hasbeen observed that a number of repair factors can be found in mitochondrial extracts. Mostof these participate in the base excision DNA repair pathway which is responsible for theremoval of simple lesions in DNA. Recent work has shown that there is efficient base excisionrepair in mammalian mitochondria and there are also indications of the presence of morecomplex repair processes. Thus, an active field of mitochondrial DNA repair is emerging. Anunderstanding of the DNA repair processes in mammalian mitochondria is an important currentchallenge and it is likely to lead to clarification of the etiology of the common mutations anddeletions that are found in mitochondria, and which are thought to cause various humandisorders and to play a role in the aging phenotype.