Dissection of affinity captured LINE-1 macromolecular complexes

Our genome consists of about two percent genes, while around 60 to 70 percent are made up of hundreds of thousands of copies of very similar DNA sequences. These repeats have accumulated over time due to specific genetic elements called transposons. Transposons are often referred to as ‘jumping genes’, as they can move within the genome and thereby create mutations that may lead to cancer or other genetic diseases. LINE-1 is the only remaining active transposon in humans, and it expands by copying and pasting itself to new locations. To do so, it is first transcribed into RNA – the molecules that help to make proteins – and then converted back into identical DNA sequences. In a never-ending battle, our cells have been fighting to keep LINE-1 and its ancestors from replicating, and so evolved various defense mechanisms. Yet, LINE-1 has learned to circumvent these barriers, and continues to replicate and cause disease. Our understanding of these defenses and of how LINE-1 evades them is limited. Previous research has shown that the LINE-1 RNA and its two encoded proteins, called ORF1p and ORF2p, interact with a series of other proteins, with which they can form different types of complexes. Now, Taylor, Altukhov, Molloy et al. used human embryonic kidney cells grown in the laboratory with different LINE-1 mutations to identify how they affect the bound proteins and RNAs. The results showed that LINE-1 can form at least two different sets of complexes with other proteins. The complex containing ORF1p and ORF2p and several other proteins was located in the cytoplasm, the fluid that fills the cells. However, the experiments also revealed a new complex in the cell nucleus, which contained ORF2p and proteins involved in DNA replication and repair, but not ORF1p. The results suggest ORF1p delivers RNPs to the nucleus around the time the cell divides. Another group of researchers has looked more closely at what happens during cell division. A next step will be to study how exactly LINE-1 contributes to cancer. In the future, overactive LINE-1 proteins could be targeted to kill cancer cells, to identify cancer early, or to see if the cancer has come back. LINE-1 may also provide clues on how the genome has evolved.