“We already knew that DNA damage triggers an alarm in our body cells”, says lead researcher Wim Vermeulen. He is a Professor of genome stability at Erasmus MC in Rotterdam, the Netherlands. “We have now shown that this alarm is also set off during transcription of damaged genes.” (Read ‘back to basics’ at the bottom of this article for a brief explanation of transcription and related biological processes.) Professor Vermeulen, together with Dr Maria Tresini and Dr Jurgen Marteijn from his team, just published their findings in the leading scientific journal Nature. Dr Tresini explains how the novel DNA damage alarm works:

Continuous attack

“Chemicals and sunlight continually damage our DNA. Damaged DNA disturbs cellular function and can cause ageing. Moreover, permanent changes in the genetic code (i.e. mutations) can arise when the DNA duplicates before the damage is repaired. Mutations may result in cancer. Fortunately, most lesions are rapidly repaired by the cell’s repair proteins. In addition, the cell turns on a DNA damage alarm when it detects DNA lesions.”

DNA damage response

“The alarm sets a variety of processes in motion. For instance, it temporarily stops DNA duplication and cell division, preventing errors from being passed on to daughter cells. But DNA damage does not only affect DNA duplication; it also has a great impact on gene transcription. The enzyme that carries out transcription halts when it encounters a UV-induced DNA lesion. Until now, it was unknown whether these transcription problems also trigger the DNA damage response. We discovered that this is indeed the case.”

ATM protein

“The key actor in the new mechanism is a protein called ‘ATM’. It has long been known that ATM has a central role in DNA damage signal transmission when DNA double-strand breaks are formed. But now we found that the ATM alarm is also triggered by UV-induced transcription halting. ATM then influences alternative splicing of gene transcripts. This leads to the formation of new protein variants that may counteract the negative effects of DNA lesions.”

Solving the puzzle

Professor Vermeulen concludes: “This is an important step towards solving the complex puzzle of how cells respond to DNA damage to protect us from ageing and cancer. Our study provides opportunities for possible intervention in these important medical problems in the future.”

Related projects and further reading

This work was partially made possible by the European Commission’s ERC Advanced grant that Professor Vermeulen received in 2013 and a Worldwide Cancer research charity fund grant from 2010. Visit the Vermeulen lab website for more information about his work.

The EU-funded project DDResponse also studies how cells respond to DNA damage.

The EU-funded project Mismatch2model studied how cells repair a specific type of DNA error called ‘DNA mismatch’.

Back to basics

“We need a basic knowledge of cell biology to understand the new discovery”, says Dr Jurgen Marteijn. He explains: “Cells are the working units of our bodies. The majority of cellular structures are made up of proteins. Proteins also perform most life functions, e.g. enzymatic reactions. The instructions on how to make proteins are encoded by the genes in our DNA.

DNA is first transcribed into RNA (transcription). RNA then functions as a template to make the protein (translation). One RNA molecule can be processed in various ways (splicing) so that a single gene can encode multiple different proteins. DNA replication is another important process; this happens during cell division. Some cells in our body divide continually. For instance, the layer of cells that lines our gut is completely renewed every five days, requiring a large number of cell divisions. DNA is duplicated during this process.”