Closing the gaps in kinetoplast DNA network replication

Abstract

Trypanosomatids are protozoan parasites responsible for important tropical diseases. One example, Trypanosoma brucei , causes African sleeping sickness, and related parasites cause Chagas disease and leishmaniasis. Because they are among the earliest-branching eukaryotes, trypanosomatids have unusual biological properties. One of their most curious features is a unique mitochondrial DNA network known as kinetoplast DNA (kDNA) (1). The kDNA network is composed of several thousand minicircles that are interlocked like the links in medieval chain mail. Also intertwined in the network are a few dozen maxicircles. See Fig. 1 for an electron micrograph of a segment of an isolated kDNA network from Crithidia fasciculata , a trypanosomatid often studied because it is nonpathogenic and easy to cultivate. The function of kDNA maxicircles, like mitochondrial DNA in conventional eukaryotes, is to encode a few gene products such as rRNA and subunits of respiratory complexes. However, the mechanism of gene expression is highly unconventional in that maxicircle transcripts must be edited to form a functional mRNA. Editing is an amazing form of RNA processing in which uridine residues are inserted or deleted at precise internal sites within the maxicircle transcripts, generating ORFs. Minicircles encode guide RNAs that are templates for editing of maxicircle transcripts. See ref. 2 for a review of editing and ref. 3 for a discussion of the evolution of kDNA and the significance of the network structure. Fig. 1. Electron micrograph of a segment of a kDNA network from C. fasciculata . Small loops are minicircles. [Reproduced with permission from ref. 1 (Copyright 2001, Elsevier Science).] In this issue of PNAS, Sinha et al. (4 …