Nuku, a family of primate retrogenes derived from KU70

Abstract

The ubiquitous DNA repair protein, Ku70p, has undergone extensive copy number expansion during primate evolution. Gene duplications of KU70 have the hallmark of long interspersed element-1 (LINE-1) mediated retrotransposition with evidence of target-site duplications, the poly-A tails, and the absence of introns. Evolutionary analysis of this expanded family of KU70-derived "NUKU" retrogenes reveals that these genes are both ancient and also actively being created in extant primate species. NUKU retrogenes show evidence of functional divergence away from KU70, as evinced by their altered pattern of tissue expression and possible translation in the human testes. Molecular modeling predicted that mutations in Nuku2p at the interaction interface with Ku80p would prevent the assembly of the Ku heterodimer. The lack of Nuku2p-Ku80p interaction was confirmed by yeast two-hybrid assay, which contrasts the robust interaction of Ku70p-Ku80p. While several NUKU retrogenes appear to have been degraded by mutation, NUKU2 shows evidence of positive natural selection, suggesting that this retrogene is undergoing neofunctionalization. Although Nuku proteins do not appear to antagonize retroviruses in cell culture, the observed expansion and rapid evolution of NUKUs could be being driven by alternative selective pressures related to infectious disease or an undefined role in primate physiology.