After 2015’s Nobel Prize in chemistry was awarded for advancements in our understanding of DNA repair, a recent Nature report characterises the mechanism in molecular detail. The implications for cancer research are vast.
Researchers in Paris, France, and Bristol, England, have leveraged recent advances in microscopy and fluorescent imaging to characterise the entire process of DNA repair at the molecular level. They were able to observe RNA polymerase, which ‘reads’ DNA and initiates its replication, as it moved along the DNA strand.
When it encountered damage inflicted by UV radiation, the enzyme stalled, and a number of proteins descended on the site. The team followed them as they acted in an ordered step-wise fashion and elucidated the critical steps of the DNA repair process: first, a protein called Mfd coordinates to RNA polymerase, then it directs a sort of relay team of UvrA, UvrB and UvrC. This deeper understanding of the mechanism could bolster efforts towards treatments for a variety of conditions.
Tumors can develop resistance to chemotherapy by activating the mechanism to repair the damage caused by the treatment, rescuing the cancerous cells; inhibition of this pathway would therefore make chemotherapy more effective. Additionally, the pathogenicity of tuberculosis appears to hinge on a protein very similar to one in DNA repair, so it could serve as a model target for this disease.
Some biotechs are already developing cancer therapies based on the inhibition of DNA repair. DNA Therapeutics, a France-based company that spun out of Institut Curie, developed single-interfering DNA (siDNA) that, you guessed it, interferes directly at the site of DNA damage to block repair selectively in cancerous cells. DNA Therapeutics was acquired on March 25th of this year by Onxeo, another French company specialising in orphan oncology therapeutics, for €2.7 million plus up to €25 million in royalties. Onxeo’s most notable success thus far is Beleodaq.
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