Opposing roles of pseudokinases NRBP1 and NRBP2 in regulating L1 retrotransposition

Abstract

Abstract Gene duplication generates gene paralogs that may undergo diverse fates during evolution, and thus serves as a potent catalyst of biological complexity. Genetic paralogs frequently share redundant functions and may also exhibit antagonistic activities by competing for common interaction partners. Here we show that the gene paralogs NRBP1 and NRBP2 oppositely regulate long interspersed nuclear element-1 (L1) retrotransposition, via influencing integrity of the L1 ribonucleoprotein complex. We demonstrate that the opposing roles of NRBP1 and NRBP2 are not results of a competitive mechanism, but rather due to targeting NRBP1 for degradation by NRBP2, probably through heterodimer formation. Moreover, our phylogenetic analysis shows that the regulatory function of NRBP2 may be acquired later during evolution, suggesting that evolutionary pressure has favored this functional fine-tuning of NRBP1. In summary, our findings not only identify NRBP1/2 as L1 regulators and implicate their involvement in human pathogenesis, but also provide a mechanistic insight into the regulatory details arising from gene duplication.