Researchers reveal mechanism of protection against cancer

Genetics

In a new paper published in Nature, researchers at the Francis Crick Institute in the UK have outlined the structure and function of a protein complex which is required to repair damaged DNA and protect against cancer.

The research could help inform the best line of treatment for people living with cancer.

People with BRCA2 mutations are predisposed to breast, ovarian and prostate cancers, which often develop at a young age.

Recent work shows that defects in several other proteins can cause inheritable breast and ovarian cancers or Fanconi anaemia, a blood disorder that can lead to different cancers, including leukaemia.

The researchers used cryo-electron microscopy to reveal the atomic structure of four of these proteins, which come together to form a complex called BCDX2. This allowed them to map mutations associated with cancer on the 3D structure, revealing the important regions of the complex, and why certain mutations prevent DNA repair, leading to an instability in a person’s genes and cancer.

Eric Liang, co-first author and Postdoctoral Fellow at the Crick, added: “Just five years ago we wouldn’t have been able to do this – the rapid advance of technology has made this research possible. DeepMind’s AlphaFold2 (a computer programme which can predict a protein’s 3D structure), cryo-EM and high-resolution imaging techniques allowed us to gather the full picture of structure and function for this key protein complex. It was a very collaborative project, spanning multiple labs and technical teams across the Crick.”

BCDX2 mutations lead to cancer

The researchers discovered BCDX2’s role in the cell, finding that it acts as a ‘molecular chaperone’ – it helps target another protein called RAD51, causing it to recognise and assemble at regions where DNA repair needs to take place. Together, BRCA2, BCDX2 and RAD51 are the main players in the process that repairs damaged DNA – called ‘homologous recombination’.

The research shows that BCDX2 is just as important for repairing DNA as BRCA2, suggesting mutations should also be routinely screened for.

Luke Greenhough, co-first author and Postdoctoral Research Assistant at the Crick, said: “For the first time, we’ve been able to show the direct links between structure, function and why mutations in any of the components of BCDX2 leads to cancer. We now understand its crucial role in DNA repair, which explains why mutations can lead to cancer.”

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