David Clynes

Cancer therapeutics, DNA damage and repair laboratory

A major focus of our work is exploring how ATRX prevents normal cells from elongating their telomeres via the ALT pathway and trying to understand the role of ATRX in DNA replication and repair.

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Research Summary

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).

Importantly, it is predicted that ALT positive cancers are susceptible to different therapeutic treatments than other cancers. This is particularly significant because a variety of childhood cancers, including currently untreatable brain tumours, extend their telomeres via the ALT pathway. To date there are no ALT-targeted therapeutics. Targeting the ALT pathway may provide a much needed new approach to treating these cancers.

Recent research has provided important clues as to how telomere lengthening is activated in ALT cancers. We have shown that expression of a protein 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 (See Figure). Understanding more about how ATRX works will provide important clues for the development or identification of new drugs that inhibit this pathway.

In addition our lab is interested in the identificatin ofnew drugs 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.


















Figure: Proposed mechanism for ATRX mediated suppression of the ALT pathway




Supervisors: Andrew Blackford, David Clynes
Supervisors: David Clynes, Andrew Blackford.


David is a Group Leader within the CRUK/MRC Oxford Institute for Radiation Oncology and Department of Oncology, based at the MR Weatherall Institute of Molecular Medicine. After obtaining his PhD in the School of Biochemistry at the University of Oxford in 2008, he undertook postdoctoral work with Richard Gibbons and Doug Higgs in the Nuffield Department of Clinical Laboratory Sciences, University of Oxford.  He has been awarded a Children with Cancer UK Paul O'Gorman Research Fellowship and took up this position in January 2017.



Clynes, Jelinska, Xella, Ayyub, Scott, Mitson, Taylor, Higgs, Gibbons. Suppression of the alternative lengthening of telomere pathway by the chromatin remodeling factor ATRX. Nature Comms. (2015) 6: p. 7538

Chen, Sook Ahn, Massie, Clynes, Godfrey, Li, Jung Park, Nangalia, Silber, Mullally, Gibbons, Green. JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response. PNAS, (2014) 111(42), 15190-15195

Howe, Sale, Boubriak, Nair, Clynes, Grijzenhout, Murray, Woloszczuk, Mellor. Lysine acetylation controls protein conformation by influencing proline isomerization. Molecular Cell, (2014) 55(5), 733-744

Clynes, Jelinska, Xella, Ayyub, Taylor, Mitson, Bachrati, Higgs, Gibbons. ATRX dysfunction induces replication defects in primary mouse cells. Plos One, (2014) 9(3), e92915. doi:10.1371/journal.pone.0092915

Clynes, Higgs, Gibbons. The chromatin remodeller ATRX: A repeat offender in human disease. Tends Biochem Sci, (2013) 38(9), 461-466

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

Eustermann, Yang, Law, Amos, Chapman, Jelinska, Garrick, Clynes, Gibbons, Rhodes, Higgs, Neuhaus. Cominatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin. Nat Struct Mol Biol, (2011) 18(7), 777-782

Pinskaya, Nair, Clynes, Morillon, Mellor.  Nucleosome remodelling and transcriptional repression are distinct functions of Isw1 in Saccharomyces cerevisiae.  Mol Cell Biol, (2099) 29(9), 2419-2430

Clynes, Walter, Tang, Marmostein, Mellor, Berger. 14-3-3 interaction with histone H3 involves dual modification pattern of phosphoacetylation. Mol Cell Biol, (2008) 28, 2840-2849

Mellor, Dudek and Clynes. A glimpse into the epigenetic landscape of gene regulation. Curr Opin Genet Dev, (2008) 18, 116-112

Macdonald, Welburn, Noble, Nguyen, Yaffe, Clynes, Moggs, Orphanides, Thomson, Edmunds, Clayton, Endicott, Mahadevan. Molecular Basis for the Recognition of Phosphorylated and Phosphoacetylated Histone H3 by 14-3-3. Molecular Cell, (2005) 20, 199-21

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