A RIDDLE and a Prize – Dr Grant Stewart and DNA repair

DNA double-strand breaks are a prime cause of cancer

At Cancer Research UK we pride ourselves on funding world-leading research, so it’s always satisfying when our scientists win prestigious awards. One recent winner was Dr Grant Stewart from the Cancer Research UK Institute for Cancer Studies in Birmingham, who has been awarded the annual Lister Institute Research Prize.

Dr Stewart recently had a paper in the journal Cell, in collaboration with scientists in Canada and France, looking at how cells repair a type of DNA damage known as ‘double-strand breaks’.

It’s an impressive piece of research, shedding light not only on a rare genetic condition called RIDDLE syndrome, but also on the development of blood cancers.

Solving the RIDDLE of double-strand break repair

Double-strand breaks happen when DNA is completely snapped in two, and it spells bad news for the cell. If left unrepaired, double-strand breaks can cause cell death. And if they’re repaired incorrectly, the wrong bits of chromosomes can get glued together, leading to potentially cancer-causing mistakes.

It’s vital that double-strand breaks are recognised correctly by the cell and repaired (correctly) as soon as possible, or that the cell is put to death by a process called apoptosis. We know it’s important because people who inherit rare genetic faults that hamper this repair process are much more likely to develop cancer. They’re also more likely to develop problems with their immune system and they are very sensitive to DNA damage caused by radiation.

One such genetic condition is RIDDLE syndrome (which stands for radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties), first described by Dr Stewart and his team in 2007.  It’s likely that the faulty gene underlying this condition is involved in double-strand break repair, but it’s none of the ‘usual suspects’, such as ATM, a gene that causes a similar syndrome called Ataxia Telangiectasia when faulty.

So Dr Stewart and his team set out to solve this RIDDLE, and discover the faulty gene responsible for the syndrome.

Hunting for faulty genes

In people who suffer from RIDDLE syndrome, a protein called 53BP1 fails to build up at the sites of double-strand breaks. This protein signals the presence of damage – it’s a ‘beacon’ that recruits other proteins to start the repair work. Stewart’s team searched for genes that, when removed, stopped this beacon from building up at damaged DNA.

He used a technique called RNA interference, which can systematically ‘knock down’ the activity of specific genes in cancer cells grown in the lab. After discounting the ‘usual suspects’, their search led them to RNF168 – a relatively unknown gene.

Further experiments revealed that RNF168 helps to recruit 53BP1 and other signalling molecules to sites of double-strand DNA breaks, alerting the cell to the presence of damage and kick-starting the repair-or-die process. They had found the prime suspect for RIDDLE syndrome, confirmed by experiments on cells taken from a patient with the condition.

What does it mean?

We inherit two copies of most of our genes – one from mum and one from dad. RIDDLE syndrome occurs in people who have two faulty versions of RNF168. But what about people with only one fault? Or who develop RNF168 faults during their lifetime?

At the moment we don’t know the answers to these questions – but the researchers think it’s likely that RNF168 plays a role in randomly occurring cancers as well as inherited syndromes like RIDDLE. For example, the father of the RIDDLE patient in this study (who presumably has one faulty copy of RNF168) developed a type of leukaemia called CLL. This may be significant, although it needs further investigation before we’re sure that RNF168 faults are involved in this disease.

The Lister award will allow Dr Stewart to continue his investigations into RNF168 for another 3 years. He was previously supported by a Cancer Research UK Career Development Fellowship that allowed him to start up his own research group.

We’ve still got a long way to go before research into this rare genetic syndrome leads to new ways to treat cancer in the general population. But by investing in fundamental cancer biology, we – and other organisations like us– are paving the way for cancer treatments of the future.

Kat

References:

Stewart, G. et al. (2009). The RIDDLE Syndrome Protein Mediates a Ubiquitin-Dependent Signaling Cascade at Sites of DNA Damage Cell, 136 (3), 420-434 DOI: 10.1016/j.cell.2008.12.042