Abstract
We report frequent losses of components of the classical nonhomologous end joining pathway (C-NHEJ), one of the main eukaryotic tools for end joining repair of DNA double-strand breaks, in several lineages of parasitic protists. Moreover, we have identified a single lineage among trypanosomatid flagellates that has lost Ku70 and Ku80, the core C-NHEJ components, and accumulated numerous insertions in many protein-coding genes. We propose a correlation between these two phenomena and discuss the possible impact of the C-NHEJ loss on genome evolution and transition to the parasitic lifestyle.IMPORTANCE Parasites tend to evolve small and compact genomes, generally endowed with a high mutation rate, compared with those of their free-living relatives. However, the mechanisms by which they achieve these features, independently in unrelated lineages, remain largely unknown. We argue that the loss of the classical nonhomologous end joining pathway components may be one of the crucial steps responsible for characteristic features of parasite genomes.
Highlights
IMPORTANCE Parasites tend to evolve small and compact genomes, generally endowed with a high mutation rate, compared with those of their free-living relatives
To fix such an extreme type of damage, cells have evolved repair mechanisms known as homologous recombination (HR) and nonhomologous end joining (NHEJ)
Unlike A-NHEJ, classical nonhomologous end joining pathway (C-NHEJ) has no enzymatic overlap with HR and in mammals is directed by five core components: Ku70/Ku80 heterodimer (Ku), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), DNA ligase IV (Lig4), and the XRCC4 and XLF proteins [6,7,8]
Summary
IMPORTANCE Parasites tend to evolve small and compact genomes, generally endowed with a high mutation rate, compared with those of their free-living relatives. Consistent with this suggestion, our comparative analysis of eukaryotic genomes lacking and containing C-NHEJ machinery revealed a mean size of 29.2 Mb for the former and 667.9 Mb for the latter, a remarkable difference of Ͼ20 times (P ϭ 1.0 ϫ10Ϫ8). Lineages provide evidence that loss of this DSB repair mechanism leads to genome compaction and, in turn, provides parasites with a number of selective advantages detailed below.
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