The new key player in the DNA repair process was discovered in the Rotterdam laboratory of Prof. Jurgen Marteijn, affiliated with the Oncode Institute. ‘When my PhD student Marit Geijer showed me the results of her experiments, I made a jump of joy. I told her that: this will enter the textbooks.’
Researchers have shown that a fourth protein plays an important role in the process of transcription-linked DNA repair. This involves repairing DNA damage during transcription. In transcription, DNA is translated into RNA – the molecule that contains instructions to make proteins. Three key players of transcription-linked DNA repair had already been established and this discovery completes this quartet of key players. This fourth player is named ELOF1. Marteijn and his colleagues published their findings in the scientific journal Nature Cell Biology.
The discovery of ELOF1 has made it clearer how cells prevent DNA damage leading to aging. This is how. Parts of our DNA contain code for proteins, the workhorses of body cells. The genetic code is read and converted into successive RNA and proteins. If DNA is damaged, for example by sunlight, the code can no longer be read properly, hence less proteins are produced.
Not all damage can be repaired, consequentially resulting in aging. Fortunately, more than 99 percent of damage done to coding sections of the DNA can be repaired. And that’s where ELOF1 and the other players come in. While DNA is read, they are busy repairing any damages.
ELOF1 turns out to be an extra special repair protein. ‘Unlike the other three key players, ELOF1 directly binds to the protein machinery that reads the DNA. This also provides explanation for why ELOF1 has a special role, because it helps the reading machine even when there is no DNA damage. But it also immediately comes to the rescue, as it were, if the reading machine gets stuck on DNA damage. If damaged DNA is not repaired properly, the reading machine gets stuck and the process get stuck. Marteijn states that ‘you can compare this to an overturned truck blocking all lanes on a motorway.’
You can rightfully call ELOF1 the guardian angel of the transcription process
Such a blockage sometimes happens in body cells as well. The jammed reading machine then blocks the protein complex passage which is involved in DNA duplication. Collisions between the reading machine and the duplication machine can lead to breaks in the DNA – one cause of cancer. ELOF1 also appears to play an important role in preventing collisions between these two protein machines. This cannot be said for the other three repair proteins. ‘With its triple role to protect the DNA reading process, you can rightfully call ELOF1 the guardian angel of the transcription process,’ Marteijn concludes.
The researchers found ELOF1 in cells of yeast, c. elegans worms and human cells. Marteijn: ‘The fact that the protein has been evolutionarily conserved so well really shows it’s importance.’
Unable to live with
But how could such an important protein remain unknown for so long? ‘The three other key players were identified by mutations in patients. The best-known example is people with Cockayne syndrome, a disease which causes body cells to age rapidly.’ However, a patient with mutations in the ELOF1 gene has never been found. Marteijn thinks there probably isn’t one. ‘We suspect that a mutation in ELOF1 has such severe consequences that one would be unable to live with it.’ Therefore, to find ELOF1, the researchers used Crispr-Cas, a relatively new genetic method which can switch off all human genes.
According to Marteijn, even after discovering ELOF1, fundamental research into DNA repair is still far from done. ‘We now know who the main players are, but there is still plenty of supporting cast to discover.’