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When it comes to cancer, how can DNA become its own enemy?

Dr Gideon Coster is one of the newest Team Leaders at the ICR. Here we take a look at his research, aiming to understand how DNA can become its own enemy.

Dr Gideon Coster in his laboratory

Image: Dr Gideon Coster in his laboratory at the ICR

The cells in your body are dividing every day, every hour, every second…

Cell division is one of the most important processes taking place in your body – and the life cycle of each cell is carefully controlled.

The operating manual of your cells is encoded by DNA. Each cell in your body packs an entire copy of the genome, which is roughly two metres long and is composed of three billion letters.

When a cell divides, it has to make an exact copy of its DNA so that each of the two new daughter cells will have the same DNA as the parent cell. This process is called DNA replication – a vital process that allows our bodies to grow and repair themselves.

DNA replication is remarkably accurate – imagine copying the entire dictionary a thousand times over in a matter of a few hours without a single mistake. This is precisely what each cell does during DNA replication.

However during our lifetime trillions of our cells divide and mistakes do creep in. Such errors can allow cells to divide and grow uncontrollably, and the result can be cancer.

Dr Gideon Coster recently joined the ICR to understand more about DNA replication – how it works and what happens when it goes wrong.

In particular, he is looking at so-called ‘repetitive DNA sequences’, in which sequences of DNA code are repeated many times over. These stretches of DNA make up as much as half of the human genome, and pose a particular challenge when a cell needs to replicate.

With your support, Dr Coster will be able to better understand the fundamental biology of our cells and contribute to improved diagnosis and prognosis for many different types of cancer.

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What are repetitive sequences of DNA?

The building blocks of our DNA are called nucleotides. There are four different DNA nucleotides, represented by the letters: A, T, C, G. Repetitive sequences refer to regions of DNA that follow a particular pattern over and over again, or have one of the nucleotides multiple times, e.g. ACG ACG ACG ACG.

DNA is normally present in our cells in a specific structure called the double helix. However, research has revealed that DNA can also adopt other three dimensional structures.

“We believe that repetitive DNA can fold onto itself into such unusual structures, and that these structures interfere with normal DNA replication” Dr Coster explains. “Yet we know remarkably little about these events which occur as cells copy these difficult regions of the genome.”

“Do these sequences interfere with DNA replication? And how do our cells resolve these challenges? If we can learn more about how DNA correctly duplicates in repetitive sequences, we can then understand how this duplication goes wrong in cancer.”

How this research could benefit bowel cancer patients

Bowel cancer is the fourth most common cancer in the UK and responsible for around 16,000 UK deaths a year. These cancers have defects in proteins in charge of checking and correcting the errors which arise from cell division.

This means these cancers are more prone to having lots of genetic alterations – which makes them harder to treat. In 15% of bowel cancer cases, unrepaired errors introduced during DNA replication are sufficient to drive the formation of a tumour.

We are excited about the potential of Dr Coster’s work to benefit patients with tumours like these.


How will Dr Coster go about researching this?

In order to understand how DNA replication deals with repetitive sequences, Dr Coster and his team recreate the entire process of DNA replication in a test tube.

“This is a hugely complex process, requiring a combination of techniques, including biochemistry, genetics, structural biology and cell based approaches. The ICR is uniquely placed to enable this cutting-edge work, because we have experts in all these areas in the same buildings – so we are perfectly placed for cross-team working,” said Dr Coster.

His team plan to use these various techniques to gain further insight into how the large protein complex which carries out DNA replication deals with repeats and other structure-forming sequences.

From there, he hopes to identify the factors that are required to prevent replication errors and reveal how they work – so we can then begin to understand how these factors fail to work in cancerous cells.

What difference will this research make?

Dr Coster's work will lead to a better understanding of how cancers can arise from replication errors. It could also tell us more about the way cancers grow and evolve – since cancer cells are prone to developing further errors in their DNA.

Cancer’s ability to evolve and resist treatment is the biggest challenge we face. Dr Coster’s work fits in with the ICR’s ambitious plans to tackle cancer evolution in our new Centre for Cancer Drug Discovery.

We are investing an initial £75 million in creating a global centre of expertise in anti-evolution therapies – which hold the promise of outsmarting cancer to improve cure rates.

We are building a new state-of-the-art drug discovery centre to create more and better drugs for cancer patients.

Find out more

The results from Dr Coster’s work we hope will in future contribute to improved diagnosis and prognosis for many different cancers.

The work may also lead him to find new approaches to treating cancer; for example, drugs which could modulate the efficiency or accuracy of DNA replication.

How our research is transforming treatments for ovarian cancer

Anne Goward, aged 54 from Canvey Island, was diagnosed with stage 3c ovarian cancer in June 2015. She initially had surgery alongside chemotherapy. But then her cancer recurred in January 2017 – and chemotherapy was no longer working for her.

Genetic testing showed she had the BRCA1 gene mutation and so she was able to be treated with a drug called olaparib.

Olaparib is a PARP inhibitor and it inhibits a particular enzyme (protein) involved in DNA repair. The development of olaparib was underpinned by 20 years of research carried out at the ICR and led it to becoming the world’s first licensed treatment targeted against an inherited genetic fault.

Anne said: “Olaparib has given me hope. I plan to make my son’s 21st birthday and I am even planning holidays! Before, I didn’t think into the future. I’m hopeful that I will have a few years chemo free and feeling good, with fewer side effects.”

Anne’s story shows how improving our understanding of fundamental principles can make a huge difference to cancer patients’ lives. We hope Dr Coster’s research could lead to further advances for patients with other types of cancer, including bowel cancer.

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