Watch lead author Harveer Dev, Wellcome Clinical Fellow in the Jackson lab, explain the findings on video 

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Researchers identify novel ‘Shieldin’ proteins that affect the response to treatment of breast cancers caused by mutations in the BRCA1 gene

The study published in Nature Cell Biology identifies the ‘Shieldin’ complex, so-called because it shields the ends of broken DNA and regulates DNA repair. Testing the levels of Shieldin in tumours could help predict whether they will respond to anti-cancer drugs called PARP inhibitors.

Breast cancer is the most common cancer in the UK, with up to 10% of hereditary cases due to inheriting a faulty cancer-causing gene, for example, mutations in the BRCA1 gene. 

Individuals with BRCA1 mutations are at high risk of developing breast cancer, and often opt for prophylactic breast removal, as was reported for Hollywood actress Angelina Jolie.

Previous research in Professor Steve Jackson’s lab (Wellcome/ Cancer Research UK Gurdon Institute, University of Cambridge) led to the development of PARP inhibitors, a new class of cancer therapy which is highly effective in treating cancers with these mutations. Unfortunately, drug resistance is a common response, and so his group set out to establish how this resistance might develop.

Using state-of-the-art CRISPR gene editing technology, the researchers scanned the human genome for factors which, when mutated, could cause drug resistance in cells that lacked BRCA1. One of these factors was the previously uncharacterised Shieldin complex.

BRCA1 is critical for performing the accurate type of DNA repair known as homologous recombination (HR). This is counterbalanced by an opposing ‘error-prone’ repair pathway known as Non-homologous end-joining (NHEJ). The researchers identified Shieldin as a new component of the NHEJ pathway. BRCA1-negative cells rely on this error-prone DNA repair pathway, which makes them susceptible to PARP inhibitors. If Shieldin is removed from these cells, the imbalance between the repair pathways is reversed, restoring the ability of the cell to perform DNA repair by HR, overcoming the toxicity of PARP inhibitors and therefore leading to drug resistance.  

Loss of Shieldin restores genome stability in BRCA1 deficiency (double mutant cells)

Professor Steve Jackson, whose group led the research, said “there is a balance between repair factors like BRCA1 which mediate error-free DNA repair, and Shieldin which acts as a barrier and must be removed to allow accurate HR”.

Lead author on the paper, Wellcome Clinical Fellow Dr Harveer Dev, explained: “In BRCA1 mutated cells, it appears as though the persistence of the Shieldin complex at DNA breaks renders these cells sensitive to PARP inhibitors. This explains why these drugs are effective in patients with BRCA1 mutations, but it also might help to explain how drug resistance can occur.” 

The researchers went on to look at tumours from breast cancer patients carrying the BRCA1 mutation. “Those tumours with normal Shieldin levels initially respond to PARP inhibitors. However, if the Shieldin levels are low, or decrease following treatment, then resistance is observed. Hence testing the Shieldin status of BRCA1 mutated tumours might be useful in predicting responsiveness to this therapy.” 

The study went on to show that resistance to PARP inhibitors can lead the same cancer cells to develop vulnerabilities to alternative cancer treatments, such as radiotherapy or platinum-based chemotherapy.

Professor Jackson concluded, “As we improve our understanding of these DNA repair networks and how they interact, we should be able to better predict the responsiveness of an individual patient’s tumour to specific therapies like PARP inhibitors, and ultimately personalise cancer therapy to achieve the maximal therapeutic response.” 

Reference

Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells

Dev H et al. (2018) Nature Cell Biology (18 July) DOI: 10.1038/s41556-018-0140-1

Contact

Lead author Dr Harveer Dev is at hsd26@cam.ac.uk

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Read the University of Cambridge news page on this story. 

Read more about research in the Jackson lab.

Watch Steve Jackson describe his lab's research in this short video.