Oxford researchers discover DNA repair protein complex important in drug resistance in cancers driven by BRCA mutations.

A team of Cancer Centre researchers lead by Associate Professor Ross Chapman have discovered a novel DNA repair protein complex called ‘Shieldin’.

Published in Nature, the paper describes the identification of ‘Shieldin’, which was shown to be essential for generating genetic diversity in antibodies produced during immune responses.

When activated following an infection or immunisation, B cells produce specialised antibodies that cause enzymes to induce multiple breaks in genes encoding the different antibody fragments. Highly specialised DNA repair proteins are essential for the generation of the deletions and mutations required to generate new antibody genes, which enables the production of antibodies with different or improved specificities towards an antigen. Researchers found Shieldin binds to specific DNA structures present at the ends of DNA breaks formed during these processes, and was essential for their repair.

Shieldin was found to link the adaptive immune system to a mutagenic DNA repair process associated with the progression of hereditary breast and ovarian cancers caused by BRCA1 mutations.

Commenting on the link between DNA, the immune system and cancer, Associate Professor Ross Chapman, lead author of the study and group leader at the Wellcome Centre for Human Genetics remarked “For some time, my lab has been puzzled over why a DNA repair pathway that normally only functions in the immune system, is also the primary pathway responsible for cancers driven by BRCA1 gene mutations. In finding Shieldin, we have taken a major step in answering this question. DNA breaks generated during antibody class-switch recombination are known to have single stranded DNA tails at their ends. The fact that Shieldin binds these structures and promotes their repair, also suggests that the recognition and repair of similar DNA structures by Shieldin when the BRCA1 protein is no longer functional, may be what leads to the mutations that cause cancer.”

The group’s findings also provide new insights into how cancer cells can become resistant to anti-cancer drugs: “PARP inhibitors are proving to be an extremely powerful drugs to treat cancers driven by BRCA mutations, however a lot of these cancers are known to then go on to develop resistance. Our work shows mutations that effect any of the four Shieldin proteins will render these cancers completely resistant to PARP inhibitors. By working out exactly how Shieldin works, we hope to identify secondary vulnerabilities in these resistant cancers, which can be exploited in anti-cancer therapies to counteract the threat of this resistance.”

Sarah Blagden Associate Professor of Experimental Cancer Medicine & Consultant Medical Oncologist, and Director of Early Phase Cancer Trials Unit & Oxford ECMC lead, emphasises the importance of the new findings: “In this paper, Ross Chapman and his team have unpicked the main method of DNA damage repair in patients with BRCA1 mutations called non-homologous end joining (NHEJ). By comparing NHEJ in different cellular processes they have shown that, in cells lacking BRCA1, NHEJ is reliant on the four-protein complex Shieldin. Not only do they indicate Shieldin is responsible for the cancers that develop in patients with BRCA1 mutations, but also that Shieldin drives resistance to PARP inhibitors. Chapman’s findings are important in our understanding of why it is that patients with BRCA1 mutations that are taking PARP inhibitors like olaparib, rucaparib or niraparib eventually become resistant to them. By providing these new insights into BRCA1 biology, they open future avenues for tackling PARP resistance and improving outcomes for BRCA1-cancer patients in the future.”

This project was funded by Medical Research Council (MRC) Grant (MR/ M009971/1) and Cancer Research UK Career Development Fellowship (C52690/A19270) awarded to J.R.C.

https://www.nature.com/articles/s41586-018-0362-1