Role of BRCA1 BRCA2 in the repair of DNA-protein Crosslinks

Efficient DNA damage repair is crucial to maintain genomic stability and, ultimately, to prevent tumourigenesis. Cells are subjected to tens of thousands of DNA damaging events daily and have therefore developed a complex DNA damage response (DDR), in order to ensure their genetic material is preserved and passed to the next generation.

Since their identification as breast and ovarian cancer predisposition genes, BRCA1 and BRCA2 have been implicated in many aspects of the DDR, including transcriptional regulation; homologous recombination (HR) mediated repair; cell cycle checkpoint activation and many others. In fact, some of these roles are still poorly understood and, possibly, some may remain to be identified
We aim to investigate the potential role of BRCA1 and BRCA2 in the repair of DNA-protein crosslinks (DPCs). DPCs are highly deleterious to living cells, as they can block essential cellular functions, such as DNA replication and transcription, as well as interfere with accessibility of DNA repair and chromatin remodelling factors. Consequently, failure to repair DPCs can result in mutations, chromatid breaks and chromosomal aberrations, leading to genomic instability and tumour development.

It is not yet clear how DPCs are repaired but several possible mechanisms have been recently emerging. Considering the diversity of DPCs that can occur within the cell, it is even possible that more than one mechanism is responsible for eliminating these structures. Indeed, some groups have identified SPRTN as a DPC-cleaving protease, which might target a large spectrum of DPCs for proteolytic digestion; others have shown that the proteasome can alleviate the cellular sensitivity to DPC inducing agents; and, intriguingly, many well-described pathways, such as nucleotide excision repair (NER), homologous recombination (HR) and the Fanconi Anemia (FA) pathway, have also been implicated in DPC repair.

Preliminary work from our group has demonstrated that BRCA1 and BRCA2 depleted cells are sensitive to different DPC inducing agents, suggesting that these proteins play an important role in DPC repair. We aim to characterise the roles of BRCA1/2 in DPC repair and establish the mechanism by which they promote genomic stability through elimination of DPCs.

ENTRY REQUIREMENTS

Candidates should have or expect to obtain a 2:1 or higher Honours degree or equivalent in a relevant biomedical or life sciences subject.

English Language

Candidates applying from countries where the first language is not English should produce evidence of their competence through a qualification such as IELTS or TOEFL score.

The minimum recommended score for the School of Medicine, Dentistry and Biomedical Science is:
• IELTS score of 6.0 with not less than 5.5 in each of the four component elements of listening, reading, speaking and writing taken within the last 2 years;
• TOEFL score of 80+ (internet basted test), taken within the last 2 years, with minimum component scores of; Listening 17, Reading 18, Speaking 20, Writing 17);
• A valid Certificate of Proficiency in English grade A or B;
• A valid Certificate of Advanced English grade A; or
• A first or upper second class honours degree from a university based in the UK, Republic of Ireland or other suitably quality assured location in a country deemed by the UK Border Agency to be majority English speaking.

For a list of English Language qualifications also accepted by the School and University please see the following link:
http://www.qub.ac.uk/International/International-students/Applying/English-language-requirements/#English

The English Language Unit (ELU) offers both pre-sessional and in-sessional courses in English for academic purposes and study skills. Courses vary in length and full information can be obtained from the ELU http://www.qub.ac.uk/tefl/