Investigating the genetic determinants of ultra-complex telomere fusion

 We are seeking a motivated molecular biologist to study the mechanisms by which telomere dysfunction impacts cancer genomes. The primary aim of this project is to understand how telomere dysfunction and fusion drives genome-wide mutation by identifying the genetic requirements for the formation of ultra-complex telomere fusion events.

Telomeres are structures that cap the ends of linear chromosomes. In human cells they are composed of the hexameric DNA sequence TTAGGG, tandemly repeated into arrays of up to 25 kb. Telomeric function is conferred by a complex of proteins, collectively referred to as the ‘shelterin’ complex, that associate with telomeres via interactions with the key TTAGGG repeat binding proteins TRF1, TRF2 and Pot1. Telomeres prevent the natural end of the chromosome from being recognised as a double-stranded DNA break and counteract the end-replication losses that occur as a consequence of the semi-conservative replication of linear DNA molecules. This function is mediated by the reverse transcriptase telomerase, that catalyses the RNA templated addition of telomere repeats de novo at the chromosomal terminus. The majority of human somatic cells do not express sufficient levels of telomerase to counteract end-replication losses, and thus telomeric sequences erode at a rate of around 60-120 bp/cell division. Short telomeres can elicit a TP53-dependent cell cycle arrest, referred to as replicative senescence, that provides a stringent tumour suppressive function. However, in the absence of a functional DDR checkpoint response, on-going cell division results in continued telomere erosion and ultimately the loss of the end-capping function. Telomeres can then be targeted for DNA repair, resulting in telomere fusion, the formation of dicentric chromosomes and the initiation of cycles of anaphase-bridging, breakage, and fusion. The ensuing cellular crisis leads to a strong selection pressure for the upregulation of telomere maintenance mechanisms, principally telomerase activity, that facilitates the escape from crisis. This process is considered a key mutational mechanism that drives genomic instability and clonal evolution during malignant progression.

We have developed single-molecule approaches to detect and characterise the DNA sequence of telomere fusion events. In doing so we have a identified a class of ultra-complex events involving multiple non-telomeric loci across the genome that resemble chromothripsis. These events appear to be mediated by mechanisms that are distinct from simple telomere-telomere fusion events. We have developed the ability to induce these events and test the underlying genetic requirements. This project will use this system to test key components of the DNA damage response pathways for their role in mediating these highly mutagenic events.

This project will provide the student with comprehensive training in molecular biology techniques including single-molecule PCR, nanopore long-read DNA sequencing, cell culture and bioinformatic analysis of complex datasets.

Entry Requirements  

Applicants should possess a minimum of an upper second class Honours degree, master’s degree, or equivalent in a relevant subject. 

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS). 

How to Apply  

This studentship has a start date of October 2024. In order to be considered you must submit a formal application via Cardiff University’s online application service.

There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2024). This will take you to the application portal. 

In order to be considered candidates must submit the following information: 

 • Supporting statement 

• CV 

• Qualification certificates 

• References x 2 

• Proof of English language (if applicable) 

International applicants are welcomed if the difference in fees can be covered.