From the sun’s UVA rays to tobacco smoke, our environment is chock-full of DNA-damaging agents that can lead to cancer. Thanks to our body’s own DNA repair mechanisms, however, the effects of many carcinogens can be reversed and prevent the formation of tumors. Now, according to a new study published in the early online edition of Proceedings of the National Academy of Sciences of the USA (PNAS), scientists from the University of Montreal and the Maisonneuve-Rosemont Hospital Research Centre have identified a new biochemical pathway which controls such DNA repair.

‘Our study is the first to identify a regulatory role for the ATR protein in a specific DNA repair system, which is called nucleotide excision repair or NER,’ says Elliot Drobetsky, senior author and associate professor of immunology and oncology at the University of Montreal. ‘NER is a critical DNA repair system that removes pieces of damaged DNA before these pieces can destroy the function of tumor-preventing proteins in the body. Characterizing how the NER system is turned on or off is critical to understanding how tumors develop. In this system, ATR is the key that turns on the repair machinery.’

ATR defective in tumor
The scientific team used cultured lung cells to investigate the role of ATR in NER function. They found that inhibiting ATR resulted in a dysfunctional NER system and, during a certain period of the cell’s growth cycle, damaged DNA was not repaired at all. What’s more, they discovered that some tumor cell lines are completely deficient in the ATR-mediated repair pathway, providing solid evidence that this protein’s DNA repair function may be pivotal in cancer development. ‘Our study reveals an original mechanism to explain how exposure to environmental carcinogens initiate and promote cancer,’ adds Dr. Drobetsky.

Chemotherapy implications
The goal of conventional chemotherapy is to kill tumor cells – leaving normal cells relatively unaffected – by damaging their DNA. Paradoxically, most chemotherapeutic drugs which are used to cure cancer are themselves powerful carcinogens that can also cause cancer.

‘As shown in the current study, a non-functional ATR pathway resulting in limited DNA repair may be characteristic of many tumor cell types, but not of normal noncancerous cells. Determining if the NER system is working in patient tumors may be an important first step to chemotherapy prescribing practices,’ says Yannick Auclair, the study’s lead author and a PhD student at the University of Montreal.

Any tumors identified as defective in ATR-mediated repair would be expected to respond extremely well to certain types of chemotherapy, because the cells in these tumors, but not normal cells in the rest of our body, should be extremely hypersensitive to chemotherapeutic drugs.

‘Our findings open a whole new area of research,’ says Dr. Drobetsky. ‘Our data harbor critical implications not only for understanding how cancer develops but also for devising new strategies to greatly improve cancer treatment.’

Release Date: November 6, 2008
Source: University of Montreal