Complex Evolution of the Mismatch Repair System in Eukaryotes is Illuminated by Novel Archaeal Genomes

Abstract

Repairing DNA damage is one of the most important functions of the 'housekeeping' proteins, as DNA molecules are constantly subject to different kinds of damage. An important mechanism of DNA repair is the mismatch repair system (MMR). In eukaryotes, it is more complex than it is in bacteria or Archaea due to an inflated number of paralogues produced as a result of an extensive process of gene duplication and further specialization upon the evolution of the first eukaryotes, including an important part of the meiotic machinery. Recently, the discovery and sequencing of Asgard Archaea allowed us to revisit the MMR system evolution with the addition of new data from a group that is closely related to the eukaryotic ancestor. This new analysis provided evidence for a complex evolutionary history of eukaryotic MMR: an archaeal origin for the nuclear MMR system in eukaryotes, with subsequent acquisitions of other MMR systems from organelles.

Keywords: Asgard Archaea; DNA repair; Eukaryotes; Mismatch repair; mutL; mutS.

Fig. 1

mutS protein tree. The eukaryotic homologues of bacterial mutS have three different sources: one associated with Asgard Archaea (nuclear mutS homologues MSH2, MSH3, MSH4, MSH5, MSH6, MSH7), one associated with Alpha-proteobacteria (mitochondrial MSH1), and another one associated with Cyanobacteria (chloroplastic MSH1)

Fig. 2

mutL protein tree. The eukaryotic mutL homologues have two distinguishable sources: the nuclear mutL homologues (MLH1, MLH3, MLH3, MLH4) are associated with Asgard Archaea, and another branch of eukaryotic mutL are associated with Cyanobacteria (chloroplast). No mitochondria-associated MutL proteins could be traced back to Alpha-proteobacteria

Fig. 3

Main events in the evolution of mismatch repair machinery composed by mutS–mutL system: Eukaryotic mutS and mutL were inherited vertically from archaeal ancestors and then acquired laterally twice upon endosymbiotic events. The transition from Archaea to eukaryotes was characterized by large-scale duplication events to produce all the nuclear paralogues; later, an acquisition from the mitochondrial ancestor, which is encoded in the nuclear genome, but is active inside the organelles, and again from the chloroplast in the photosynthesizing eukaryotes, also encoded in the nuclear genome, but active inside de organelles. Heimdallarchaeota is sister group to all eukaryotic nuclear paralogues. Archaeal groups themselves seem to have laterally acquired the mutS–mutL system from some bacterial donor once or more