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Targeting the Microcephalin-1 Tumour Suppressor Protein in Cancer (REF: RDF22/HLS/APP/JOWSEY)


   Faculty of Health and Life Sciences

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  Dr Paul Jowsey, Dr S Veuger  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Microcephalin-1 (MCPH1) is a tumour suppressor protein that is down-regulated in multiple cancer types. This project will investigate whether MCPH1-deficiency in cancer can be targeted therapeutically by focusing on two cellular roles of MCPH1:

1) MCPH1 and homologous recombination repair (HRR). Cells lacking MCPH1 are deficient in HRR, a pathway that repairs DNA double strand breaks (DSBs). Previous studies have demonstrated that HRR-deficiency can be targeted therapeutically by the inhibition of other DNA repair pathways and/or inhibitors of DNA damage checkpoint signalling (the mechanisms that bring about arrest of the cell cycle in the presence of DNA damage). This effect is known as synthetic lethality – where lack of one cellular pathway is tolerated but simultaneous loss of an additional pathway leads to cell death. For example, tumours lacking the BRCA1 or BRCA2 tumour suppressor proteins (both involved in HRR) are killed by inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1, needed for the base excision repair pathway), whilst normal cells are not. We predict that MCPH1-deficient cells will be killed by PARP-1 inhibitors and will also explore other inhibitors that have demonstrated synthetic lethality in HRR-deficient tumours. 

2) Cells lacking MCPH1 show the unusual phenotype of premature chromosome condensation (PCC) before cells enter mitosis – normally this would occur in prophase (the first stage of mitosis). In an asynchronous culture of MCPH1-deficient cells, around 10-15% of cells display the PCC phenotype. In the condensed state, DNA is extremely tightly-packed and we predict this will hinder both DNA repair and DNA replication. In support of this prediction, an important aspect of normal DNA repair and replication is actually relaxation of the local DNA structure to allow access of key protein complexes. This section of the project has three main aims:

(i) Investigate the sensitivity of MCPH1-deficient cells to a range of DNA damaging cancer therapeutics with diverse modes of action (including alkylating agents, crosslinking agents and drugs that act specifically during DNA replication). 

(ii) Investigate ways to increase the % of MCPH1-deficient cells showing the PCC phenotype, thus increasing the number of cells with tightly-packed DNA that is likely resistant to DNA repair. Our preliminary studies using cell synchronisation methods have achieved >80% of MCPH1-deficient cells with PCC – we will investigate how this impacts on cell survival after a range of DNA damaging agents [e.g. those used in section (i) above] and predict increased cytotoxicity after DNA damage.

(iii) Investigate the signalling mechanisms that cause the PCC phenotype. We have identified several novel sites of MCPH1 acetylation and phosphorylation and will investigate (a) how these impact upon the regulation of chromosome condensation by MCPH1 and (b) the upstream signalling enzymes that target these sites in MCPH1 (e.g. by using specific inhibitors). Such studies will increase our understanding of MCPH1 function/regulation and could identify novel routes for therapeutic intervention.

Techniques to be used include cell culture, gene knockdown (using both short interfering RNA and CRISPR gene editing), PCR/mutagenesis, immunoassays, fluorescence microscopy, DNA damage assays and cytotoxicity assays.

Eligibility and How to Apply:

Please note eligibility requirement:

·      Academic excellence of the proposed student i.e. 2:1 (or equivalent GPA from non-UK universities [preference for 1st class honours]); or a Masters (preference for Merit or above); or APEL evidence of substantial practitioner achievement.

·      Appropriate IELTS score, if required.

·      Applicants cannot apply for this funding if currently engaged in Doctoral study at Northumbria or elsewhere or if they have previously been awarded a PhD.

For further details of how to apply, entry requirements and the application form, see

https://www.northumbria.ac.uk/research/postgraduate-research-degrees/how-to-apply/ 

Please note: All applications must include a covering letter (up to 1000 words maximum) including why you are interested in this PhD, a summary of the relevant experience you can bring to this project and of your understanding of this subject area with relevant references (beyond the information already provided in the advert). Applications that do not include the advert reference (e.g. RDF22/…) will not be considered.

Deadline for applications: 18 February 2022

Start Date: 1 October 2022

Northumbria University takes pride in, and values, the quality and diversity of our staff and students. We welcome applications from all members of the community.

Informal enquiries to Dr Paul Jowsey ([Email Address Removed]).


Funding Notes

Each studentship supports a full stipend, paid for three years at RCUK rates (for 2021/22 full-time study this is £15,609 per year) and full tuition fees. UK and international (including EU) candidates may apply.
Studentships are available for applicants who wish to study on a part-time basis over 5 years (0.6 FTE, stipend £9,365 per year and full tuition fees) in combination with work or personal responsibilities.
Please also read the full funding notes (https://www.northumbria.ac.uk/research/postgraduate-research-degrees/studentships/rdf) which include advice for international and part-time applicants.

References

Ahmadimanesh M, Abbaszadegan MR, Morshedi Rad D, Moallem SA, Mohammadpour AH, Ghahremani MH, Farid Hosseini F, Behdani F, Akhondpour Manteghi A, Jowsey P, Shabani Behbahani F, Moallem SMH, Etemad L.J (2019). Effects of selective serotonin reuptake inhibitors on DNA damage in patients with depression. Psychopharmacol. 2019 Nov;33(11):1364-1376. doi: 10.1177/0269881119874461. Epub 2019 Sep 26
Li J, Dang N, Martinez-Lopez N, Jowsey PA, Huang D, Lightowlers RN, Gao F, Huang JY (2019). M2I-1 disrupts the in vivo interaction between CDC20 and MAD2 and increases the sensitivities of cancer cell lines to anti-mitotic drugs via MCL-1s. Cell Div. 2019 Jun 15;14:5. doi: 10.1186/s13008-019-0049-5. eCollection 2019.
Kyriakou S, Cheung W, Mantso T, Mitsiogianni M, Anestopoulos I, Veuger S, Trafalis DT, Franco R, Pappa A, Tetard D, Panayiotidis MI (2021). A novel methylated analogue of L-Mimosine exerts its therapeutic potency through ROS production and ceramide-induced apoptosis in malignant melanoma. Invest New Drugs. 2021 Aug;39(4):971-986. doi: 10.1007/s10637-021-01087-5. Epub 2021 Feb 23.
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