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Understanding and targeting telomere maintenance in cancer

Clynes lab 1

 

About the Research


Cancer occurs through the uncontrolled growth and division of cells, which eventually leads to the development of a tumour. The number of times a cell can divide is limited by the length of specialised DNA sequences found at the end of chromosomes. These specialised sequences are called telomeres, and in normal cells they shorten with every cell division. For a cell to become cancerous it has to stop its telomeres shortening, which in turn allows the cell to continue to grow and divide. To accomplish this, cancer cells either activate an enzyme (telomerase) that adds telomeric DNA sequences to the ends of the DNA molecules, or they copy telomeric sequences from the end of one DNA molecule to another (the alternative lengthening of telomeres (ALT) pathway). The Clynes laboratory is focused on understanding the molecular mechanisms that underpin the ALT pathway and identifying new approaches to target cancer cells that use the ALT pathway. This is achieved using a variety of cutting-edge molecular biology techniques including; genome editing using CRISPR-Cas9 technology and super-resolution microscopy.


Recent research has provided important clues as to how telomere lengthening is activated in ALT cancers. We have shown that expression of a protein called ATRX, which is inactivated in most ALT cancers, suppresses telomere lengthening in ALT cells, and this suppression is likely linked to the role of ATRX in DNA replication/repair. Understanding more about how ATRX works will provide important clues for the development or identification of new drugs that inhibit this pathway. It has also recently become apparent that the telomere lengthening that occurs in ALT cancer cells is a result of the aberrant repair of DNA damage. Indeed, telomeres present a very specialised environment for the repair of DNA damage and the lab has a major interest in learning how DNA damage at telomeres is normally repaired.


Although relatively rare in cancers overall, ALT is prevalent in a specific subset of cancers including; pancreatic neuroendocrine tumours, sarcomas and several cancers of the central nervous system such as gliomas. Many of these cancers have an extremely poor prognosis and therefore our lab is interested in the identification of new drugs and approaches that could potentially be used to target ALT cancer cells.  The challenge of identifying new cancer drugs can be approached in different ways.  One way is understanding which gene and proteins underpin an abnormal characteristic of a cancer cell (in this case aberrant telomere lengthening or the lack of ATRX) to identify new targets for the rational design of drugs.  A second ways is screening pre-existing drug libraries and testing them for their ability to limit the growth of, or preferentially kill, ALT cancer cells that lack ATRX.


Projects to be offered can cover either of these key areas, or potentially include a combination of both.

For further information please contact david.clynes@oncology.ox.ac.uk.

 

 

Training Opportunities

Students will have the opportunity to learn several cutting-edge techniques including genome engineering using CRISPR-Cas9, immunofluorescence and super resolution microscopy.

Students will receive extensive training in all the techniques they will require to complete their project with support from the WIMM Genome Engineering and Wolfson Imaging Centre facilities for genome engineering and microscopy work respectively.

 

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

Publications

Clynes et al., 2015. Suppression of the Alternative Lengthening of Telomere pathway by the chromatin remodeling factor ATRX.  Nature Communications 6 7538

Clynes et al, 2014. ATRX dysfunction induces replication defects in primary mouse cells. Plos One, 9(3), e92915.

Clynes, Higgs, Gibbons. 2014. The chromatin remodeller ATRX: A repeat offender in human disease. Trends Biochem Sci, 38(9), 461-466

Clynes, Gibbons. 2013.  ATRX and the replication of structured DNA. Curr Opin Genet Dev, 23(3), 289-94

Nguyen et al., 2017. The chromatin remodelling factor ATRX suppresses R-loops in transcribed telomeric repeats. EMBO Reports, 18(6), 914–928.

Lovejoy et al., 2012. Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway. PloS Genetics 8(7) e1002772