A team of scientists has discovered a new type of DNA repair mechanism that cancer cells use to recover from next-generation heavy ion cancer radiation therapy. Their results are published in the journal Nucleic Acids Research.
Ionising radiation (IR) therapy is frequently used in the treatment of cancer and is believed to destroy cancer cells by inducing DNA breaks. The newest type of radiation therapy harnesses radiation produced by a particle accelerator, which consists of charged heavy particles such as carbon ions. The particle accelerator accelerates the carbon ions to about 70% of the speed of light, which collides with and destroys the DNA of cancer cells.
These ions have a high linear energy transfer (LET) and release most of their energy within a short range, called the Bragg peak. The next-generation cancer radiotherapy works by focusing the Bragg peak on the tumour, which has the added benefit of minimising damage to surrounding normal tissues compared to the commonly used low LET radiation such as gamma or x-rays.
DNA lesions generated by heavy ion bombardment (high LET radiation) are more “complex” than those induced by traditional radiation therapy (low LET radiation). The former carries additional DNA damage such as apurinic/apyrimidinic (AP) site and thymine glycol (Tg) in close proximity to the double-strand breaks (DSB) sites, which is far more difficult to repair than ordinary DNA damage. As a result, the advanced therapy is more cytotoxic per unit dose than low LET radiation.
This makes next-generation radiation therapy a potent weapon against cancer cells. However, it has not been fully investigated how these high LET-induced lesions are processed in mammalian cells, as DNA damage from heavy ion bombardment is a process that seldom occurs on Earth (though astronauts are subject to this in space). Figuring out the complex DSB repair mechanism is an attractive research interest since blocking the cancer cells’ repair mechanism can allow the new radiation therapy to become even more effective.
The researchers visited the QST hospital in Japan to use the synchrotron named HIMAC (Heavy Ion Medical Accelerator in Chiba), which has the ability to produce high LET radiation.
The research team discovered that DNA polymerase θ (POLQ) is an important factor when repairing complex DSBs such as those caused by heavy-ion bombardment. POLQ is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). This TLS activity was found to be the biologically significant factor that allows for complex DSB repair.
Ms SUNG Yubin, one of the joint first authors, explains, “We provided evidence that the TLS activity of POLQ plays a critical role in repairing hiLET-DSBs. We found that POLQ efficiently anneals and extends substrates mimicking complex DSBs” .
The researchers also discovered that preventing the expression of POLQ in cancer cells greatly increased their vulnerability to the new radiation treatment.
“We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation,” explains Mr. YI Geunil, another joint first author .
The research team used biochemical techniques and Fluorescence Resonance Energy Transfer (FRET) to find out that POLQ protein can effectively repair synthetic DNA molecules that mimic complex DSB. This means that POLQ can be a possible new drug target to increase the cancer cells’ vulnerability against complex radiation damage.
Source: Institute for Basic Science