A conserved role for the ESCRT membrane budding complex in LINE retrotransposition.

Axel V Horn,Ivana Celic,Jeffrey S Han,Irena Martirosyan,Chun Dong,Harmit S Malik

doi:10.1371/journal.pgen.1006837

Abstract

Long interspersed nuclear element-1s (LINE-1s, or L1s) are an active family of retrotransposable elements that continue to mutate mammalian genomes. Despite the large contribution of L1 to mammalian genome evolution, we do not know where active L1 particles (particles in the process of retrotransposition) are located in the cell, or how they move towards the nucleus, the site of L1 reverse transcription. Using a yeast model of LINE retrotransposition, we identified ESCRT (endosomal sorting complex required for transport) as a critical complex for LINE retrotransposition, and verified that this interaction is conserved for human L1. ESCRT interacts with L1 via a late domain motif, and this interaction facilitates L1 replication. Loss of the L1/ESCRT interaction does not impair RNP formation or enzymatic activity, but leads to loss of retrotransposition and reduced L1 endonuclease activity in the nucleus. This study highlights the importance of the ESCRT complex in the L1 life cycle and suggests an unusual mode for L1 RNP trafficking.

Highlights

Long Interspersed Nuclear Elements (LINEs) are an ancient class of non-long terminal repeat retrotransposable elements widely dispersed among eukaryotes
The LINE-encoded replication machinery is used by other retrotransposons, and in total, has been responsible for the generation of over 1/ 3 of human DNA sequence
We show that the endosomal sorting complex required for transport (ESCRT) complex plays a conserved role in LINE retrotransposition in both yeast and humans

Summary

Introduction

Long Interspersed Nuclear Elements (LINEs) are an ancient class of non-long terminal repeat (non-LTR) retrotransposable elements widely dispersed among eukaryotes. These elements can be categorized into distinct clades based on homology of conserved domains [1]. The L1 clade is of particular interest because its namesake element, L1, is widespread throughout mammalian genomes. Other human retrotransposons such as Alu and SVA depend on the L1 machinery to replicate [3,4,5]. When the sequences of these L1 “parasites” are taken into account, greater than 30% of the human genome has been produced by the L1 retrotransposition machinery [2]

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