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Repairing DNA Damage in Response to BRAF Mutation


Project Description

We are the leading thyroid cancer research group in the UK; we work on other neoplasias as well, including breast and head and neck etc. Our main current focus lies in improving the treatment of thyroid cancer for patients, especially those with aggressive disease. The most common mutation in thyroid cancer in the V600EBRAF mutation. Our recent data suggest that the V600EBRAF mutation induces the oncogene PBF, which we have shown binds p53 and induces DNA damage.

We hypothesise that PBF suppresses activation of the replication stress response and HR-dependent repair of damaged replication forks. As a result, this renders cells genomically unstable. Consequently, patients with the BRAFV600E mutation and high PBF expression (as well as its functional partner PTTG) will have a significantly worse prognosis. We suggest that therapeutically targeting the phosphorylation of PBF (Y174), which is a critical post-translational modification regulating protein-protein interactions, will overcome the effect of the BRAFV600E mutation on tumour progression.

Based on these ideas and preliminary data in this PhD project we aim to:
1. Investigate how BRAF mutation causes replication stress-associated genome instability in an in vivo model of thyroid cancer and
2. Ascertain whether suppression of PBF activity using clinically-relevant small molecule inhibitors can overcome BRAF-driven tumourigenesis.

This project will involve leading edge molecular approaches in tumour cells and, pending sufficient progress, in mouse models of thyroid cancer. Applicants will receive a broad training in multiple techniques and will join an established and successful research group.

Person Specification
Applicants should have a strong background in molecular or cellular biology, preferably with an interest in cancer and cell signalling. They should have a commitment to PhD research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a biological subject.

Informal enquiries should be directed to Professor Chris McCabe, email

To be considered for this studentship, please send the following documents to Viktorija Ziabliceva, email :
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

Self-funded applications only.

References

1. Read ML… and McCabe CJ. 2018. Cancer Research 78(20):5863-5876 [I.F. = 9.1]
2. Read ML… and McCabe CJ. 2017. Oncogene 36(37):5296-5308 [I.F. = 7.5]
3. Watkins RJ… and McCabe CJ. 2016. J Clin Endocrinol Metab (12):4551-4563 [I.F. = 5.5]
4. ML Read… and McCabe CJ. 2011. Cancer Research 71(19):6153-64 [I.F. = 9.1]
5. RJ Watkins… and McCabe CJ. 2010. Cancer Research 70(9); 3739-49 [I.F. = 9.1]

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