Identifying if this pathway is defective may help with chemotherapy decisions, according to PNAS paper.
Researchers report locating a new biochemical pathway that controls DNA repair. They identified a regulatory role for the Ataxia telangiectasia and Rad3 related (ATR) protein in a specific DNA repair system called nucleotide excision repair (NER).
The team also discovered that some tumor cell lines are completely deficient in ATR-mediated NER. They offer this as evidence that the DNA repair function of ATR may be pivotal in cancer development.
“NER is a critical DNA repair system that removes pieces of damaged DNA before these pieces can be converted into genetic mutations that destroy the function of tumor-preventing proteins in the body,” says Elliot Drobetsky, Ph.D., senior author of the study and associate professor of immunology and oncology at the Université de Montréal.
“Characterizing how the NER system is turned on or off is critical to understanding how tumours develop. In this system, ATR is the key that turns on the repair machinery,” Dr. Drobetsky notes.
The investigators used cultured lung cells to research the role of ATR in NER. They found that inhibiting ATR resulted in a dysfunctional NER system and during a very critical period of the cell’s growth cycle, damaged DNA was not repaired at all. “Our study reveals an original mechanism to explain how exposure to environmental carcinogens initiate and promote cancer,” adds Dr. Drobetsky.
The study also shows that a nonfunctional ATR pathway resulting in limited DNA repair may be characteristic of many tumor cell types but not of normal noncancerous cells, according to the scientists.
Determining if the NER system is working in patient tumors may therefore be an important first step to chemotherapy prescribing practices, they suggest. Any tumors identified as defective in ATR-mediated repair are expected to respond well to chemotherapy, because the cells in these tumors would be extremely hypersensitive to certain anticancer drugs unlike normal cells in the rest of the body, the researchers explain.
The article, constructed by scientists from the Université de Montréal and the Maisonneuve-Rosemont Hospital Research Centre, was published in the early online edition of Proceedings of the National Academy of Sciences.