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Identification and functional characterisation of BRIT1 and MCPH1 synthetic lethal genes to treat breast and ovarian cancer

PGR-P-63

Key facts

Type of research degree
PhD
Application deadline
Ongoing deadline
Country eligibility
International (open to all nationalities, including the UK)
Funding
Non-funded
Additional supervisors
Dr Sandra Bell, Professor Colin Johnson
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

Women who have undergone surgery for breast and ovarian cancer often have additional chemotherapy to kill residual cancer cells and prevent recurrence. Unfortunately, 30-40% of these patients&rsquo; tumour cells are resistant to these treatments.

<h2 class="heading hide-accessible">Full description</h2>

<p>We have identified reduced expression of BRIT1/MCPH1, a DNA damage response gene in a third of ovarian and breast cancer patients. These reductions were associated with increasing tumour grade and poor survival1-2. Recently we have performed two complementary large-scale druggable genome siRNA screens to identify BRIT1/MCPH1 synthetic lethal (SL) genes. SL genes are when mutations in one gene alone has no effect on cell viability, however, mutation in both genes leads to cell death. Thus, targeting a SL gene in a cancer with BRIT1/MCPH1 mutations should selectively kill the cancer cells but not normal cells.</p> <p>Analysis of cell viability data from the two siRNA screens, one with BRIT1/MCPH1 knockdown the other without has been performed identifying a number of interesting candidate genes (including other DNA repair genes) which preferentially kill BRIT1/MCPH1 deficient cells. The top SL genes will be selected based on functional relevance and the commercial availability of chemotherapeutic drugs and/or small molecule inhibitors to these targets. Four individual, deconvoluted siRNAs will be used to validate potential SL hits. Functional studies will be performed to investigate the mechanism causing SL in BRIT1/MCPH1 deficient cells.</p> <p>Potential biomarkers much as BRIT1/MCPH1 will enable us to identify new chemotherapeutic approaches to treat cancer patients that are resistant to current treatments.</p> <p>Environment:<br /> You will be based in the Leeds Institute of Medical Research (LIMR), School of Medicine, University Of Leeds. This project will provide research training in a range of techniques including siRNA gene knockdown, cell culture, RNA extraction, pathway analysis, Real time PCR, immunofluorescence, western blotting, live cell imaging, DNA repair assays and drug cytoxicity assays.</p>

<h2 class="heading">How to apply</h2>

<p>Applications can be made at any time. To apply for this project applicants should complete a<a href="https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form"> Faculty Application Form</a> and send this alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates to the Faculty Graduate School <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If you have already applied for other projects using the Faculty Application Form this academic session you do not need to complete this form again. Instead you should email&nbsp;<a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a> to inform us you would like to be considered for this project.</p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p> <p><em>We welcome applications from all suitably-qualified candidates, but UK black and minority ethnic (BME) researchers are currently under-represented in our Postgraduate Research community, and we would therefore particularly encourage applications from UK BME candidates. All scholarships will be awarded on the basis of merit.</em></p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &acirc;&euro;&cent; British Council IELTS - score of 6.5 overall, with no element less than 6.0 &acirc;&euro;&cent; TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

<h2 class="heading">Contact details</h2>

<p>For further information please contact the Graduate School Office<br /> e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>