Elusive tumour suppressor protein function uncovered

16 July 2015

Central to DNA repair by homologous recombination is an elegant structure called the Rad51 filament. A number of tumour suppressor proteins and protein cousins of Rad51 influence the Rad51 filament structure to make DNA repair more efficient.

Image: Central to DNA repair by homologous recombination is an elegant structure called the Rad51 filament. A number of tumour suppressor proteins and protein cousins of Rad51 influence the Rad51 filament structure to make DNA repair more efficient. This paper shows that two of these, called RFS-1 and RIP-1, ‘remodel' the filament to a more stable, flexible and open structure in which the DNA is more accessible. ©  The image is an original illustration by Lucas Perez Trujillo (2015).

A study led by Francis Crick Institute researchers describes the long sought after biochemical function of an important family of tumour suppressor proteins.

Called 'Rad51 paralogs', when they're mutated in humans, these proteins cause breast and ovarian cancer and Fanconi anemia - a genetic disease that causes leukaemia and bone marrow failure in most sufferers, alongside other problems.

Dr Martin Taylor of the Crick (currently based at Clare Hall in Hertfordshire) explained: "The biochemical function of these proteins has eluded scientists for two decades, because they are very difficult to work with in many organisms. However we chose to use a nematode worm as a model organism and discovered that the proteins were much easier to study."

Using a range of cutting edge biochemical and biophysical techniques allowed the scientists to discover that Rad51 paralogs have an important function in stimulating a DNA repair reaction called homologous recombination, by an unexpected molecular mechanism. DNA repair is a critical process in cells - when it fails, unrepaired mutations in the DNA can cause cells to lose normal controls on their growth and behaviour. This can result in tumours forming.

Dr Simon Boulton of the Crick (also at Clare Hall) said: "Homologous recombination is an essential mechanism for the repair of DNA double strand breaks. It is tightly regulated at each step of the reaction by mediator proteins, including the well known tumour suppressor proteins BRCA1 and BRCA2, as well as the Rad51 paralogs. 

"The importance of homologousrecombination in human disease is highlighted by the fact that mutations in any of these proteins can cause a severe form of Fanconi anaemia,  as well as hereditary breast and ovarian cancers." 

He added: "The Rad51 paralogs are just as important as BRCA1 and BRCA2 but are much less well known because, until now, we didn't understand how they worked."

At the heart of DNA repair by homologous recombination is a protein called Rad51, which can form filamentous structures wrapped around DNA. These structures initiate the DNA repair process. The Rad51 paralogs are cousins of Rad51.

The scientists found that Rad51 paralogs bind these Rad51-DNA filaments and alter their structure, making it more flexible, stable and open. This molecular switch makes Rad51 much more efficient at DNA repair by homologous recombination. This mechanism was completely unanticipated and adds a new level of complexity to our understanding of how homologous recombination is controlled.

It's hoped that understanding how this important group of tumour suppressor proteins works will help scientists understand the cause of the diseases that result when the proteins are mutated.

The paper, Rad51 paralogs remodel pre-synaptic Rad51 filaments to stimulate homologous recombination, is published in Cell.

  • Research led by Francis Crick Institute researchers has uncovered the biochemical function of a family of tumour suppressor proteins that has eluded scientists for two decades.
  • Similarly to the well known breast and ovarian cancer-linked proteins BRCA1 and BRCA2, these proteins, called 'Rad51 paralogs' play a role in a DNA repair process called homologousrecombination.
  • The work was done in collaboration with researchers at Masaryk University in Brno, Czech Republic, the MRC Clinical Sciences Centre at Imperial College London and the University of Virginia in the USA.