Yeast 'DNA damage sensor' provides chemotherapy resistance clue

Cancer Research UK scientists have been part of an international collaboration that has revealed the structure of a protein found in simple yeast cells and shown how it flags up damaged DNA for repair. The results of their study are published in Nature*. The finding may provide clues as to how some cancer cells become resistant to certain chemotherapy drugs.

Researchers based at Cancer Research UK's Paterson Institute for Cancer Research at the University of Manchester, worked with other US and UK collaborators to investigate a recently discovered DNA 'damage sensing' protein family. The collaboration used a technique called X-ray crystallography to show in yeast cells how the family called alkyltransferase-like proteins (ATLs) - originally discovered by Paterson scientists*** - can detect the DNA damage caused by some anti-cancer drugs, and alert the cell's DNA repair machinery.

They also found ATLs in organisms as diverse as sea anemones and microscopic organisms - so it's likely that a similar protein plays the same kind of 'damage sensor' role in humans.

Some anti-cancer drugs kill tumour cells by damaging their DNA. But sometimes the treatment fails because tumour cells can repair this DNA damage - and reverse the effects of the drug.

This latest study suggests that that ATL proteins might contribute to this drug resistance. Their new work shows how the yeast ATL protein binds to DNA and 'flips' out the damaged DNA bases, flagging them up for repair.

The scientists already knew that the ATL in yeast cells protect them from being destroyed by the kind of damage caused by anticancer agents. When the gene for the ATL protein was deactivated in yeast cells, the yeast cells became very sensitive to these drugs.

The study of the DNA repair processes in cells is an area of intense activity. A better understanding of them will help scientists find ways to block DNA repair which could lead to the development of more effective cancer treatments. A number of clinical trials based on this concept are being carried out at the moment.

Doctor Geoff Margison, Cancer Research UK scientist and study co-author, said: "We have found out how this family of proteins can begin the repair of certain types of DNA damage.

"Now the hunt is on to see if similar processes exist in humans. If so, they may tell us why some tumours do not respond to certain chemotherapy drugs and they will provide important new targets for future drug development."

Dr Helen George, Cancer Research UK's head of science information, said: "Our research over several decades has contributed to our understanding of repair kits in cells and these latest results are an exciting step forward. Many chemotherapy drugs work by damaging the DNA in cancer cells which destroys them. But cells can be incredibly resilient and fight back to repair their damage.

"This research reveals for the first time exactly how a key repair protein can detect the damage caused by some types of chemotherapy and initiate the DNA repair process. If this process occurs in humans, this may provide new leads for treating cancer."

Notes:

*Alkylated DNA damage flipping bridges base and nucleotide excision repair. Nature. Julie Tubbs et al.

** X-ray crystallography
This technique is used to determine molecular structures by finding out the order in which atoms are arranged within a crystal. X-rays are beamed onto a crystallised form of the molecule of interest and are scattered in different directions. By following the direction in which the x-rays are scattered it is possible to produce a 3-D structure of the location of the atoms in the crystal and from this determine the 3-D structure of the molecules.

***In 2003-2007 they first reported and then characterised the fission yeast ATL protein and reported that inactivation of the gene (called Atl1) in S.pombe made them very sensitive to DNA damaging agents.

Margison GP, Povey AC, Kaina B, Santibanez Koref MF. Variability and regulation of O6-alkylguanine-DNA alkyltransferase. Carcinogenesis. 24: 625-635. (2003)

Pearson SJ, Ferguson J, Santibanez-Koref M, Margison GP. Inhibition of O6-methylguanine-DNA methyltransferase by an alkyltransferase-like protein from Escherichia coli. Nucleic Acids Res. 33: 3837-3844 (2005)

Pearson, S.J., Wharton, S.J., Watson, A.J., Begum. G., Butt, A., Glynn, N., Shibata, T., Williams, D.M. Santibanez-Koref, M.F., Margison, G.P. A novel DNA damage recognition protein in S. pombe. Nucleic Acids Res. 34: 2347-2354 (2006)

Margison, G.P., Butt, A., Pearson, S.J., Wharton, S.J., Watson, A.J., Marriott, A., Caetano, C.M., Hollins, J.J., Rukazenkova, N., Begum, G. and Santibanez-Koref, M.F. Alkyltransferase-like proteins. DNA Repair 8; 1222-1228 (2007).