Nuclear and Kinetoplast DNA Replication in Trypanosomatids

Trypanosomatids are among the most primitive eukaryotes and therefore exhibit both conserved and unique non-conserved features in the DNA replication machinery. In eukaryotes, nuclear DNA replication is preceded by the assembly of the pre-replication complex (pre-RC), which is coordinated by the six-subunit origin recognition complex (ORC), which together with the Cdc6 and Cdt1 proteins play a central role in the loading of the hetero-hexamer Mcm(2-7). In the domain Archaea there are no Cdt1 protein homologs, Mcm is a homo-hexamer, which is recruited by a protein that shows homology with ORC, and Cdc6 (called Orc/ Cdc6). Curiously, trypanosomatid pre-RC differs from others eukaryotes in this context, and it appears more similar to that of Archaea, presenting a homolog of protein Orc/Cdc6 and no homologs of Cdt1, in addition to present Mcm as a hetero-hexamer complex. The completion of DNA replication, at trypanosomatid telomeres, apparently is similar to other eukaryotes, although the processing of the leading and lagging telomeres required to generate the 3' overhangs, which serves as telomerase substrate, remains unknown. With the generation of overhangs at the ends of the chromosomes, telomeres are frequently extended by the action of telomerase, whose control also remains unknown. It is worth mentioning that DNA replication in trypanosomatids initiates almost simultaneously in the nucleus and the kinetoplast, suggesting that regulation of DNA synthesis in the two DNA-containing organelles may be coordinated. The kinetoplast DNA (kDNA) consists of mini- and maxicircles, which are replicated by many proteins whose mechanisms of action remain unclear. This chapter aims to review and discuss the complex DNA replication mechanisms that act independently in the kinetoplast and the nucleus, as well as some fascinating peculiarities exclusive to trypanosomatids protozoa group.