A new window to DNA repair mechanism and cancer therapy
13 Aug 2018
By Dr. Benu Brata Das, Intermediate Fellow
Indian Association For the Cultivation of Science (IACS), Kolkata
The entire genome containing the blue print of life remains tightly packaged within the nucleus of a cell. Cutting the DNA serves as the primary step for cracking the enigmatic code for sustaining life. These are catalyzed by "biological scissors" known as topoisomerases. This enzyme precisely snips the DNA, thereby releasing the torsional stress of a highly coiled DNA, or, untangling an entangled strand, and then swiftly pastes the break. Spontaneous damages to the genome can cause these enzymes to generate breaks but not to reseal them. These breaks, if left unmonitored, can lead to complete chemical chaos, thereby, serving as a precursor to cancer formation. DNA, therefore, must be under constant surveillance and repair mechanisms for efficient maintenance of structural integrity and functional stability. This requires a plethora of DNA damage response proteins to act in a coordinated fashion. The fine tuning of their activities are governed by post translational modifications, or, in simpler words attaching chemical tags to proteins which have the ability to alter the proteins' function.
A study by our group in collaboration with Yves Pommier at National Cancer Institute, USA, recently published in Nucleic Acids Research, unravels the novel role of a protein, Protein Arginine Methyltransferase (PRMT 5), in response to anticancer drug camptothecin-mediated DNA damage. PRMT5 catalyzes addition of symmetric dimethyl group to specific arginine residues (Arg361 and Arg586) of Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key enzyme responsible for the repair of DNA topoisomerase 1 (Top1) induced DNA damage.
Our study discovered the role of TDP1arginine methylation in controlling its interaction with other DNA repair proteins like XRCC1 (X-ray repair cross-complementing protein 1) and recruitment of the repair factory at the site of the DNA damage. They also provide evidence that TDP1 methylation increase its catalytic (3' DNA phosphodiesterase) activity. Cells deficient in PRMT5 are hypersensitive to DNA damaging agents including Camptothecin.
Independent research from different groups implicate the essential a role of PRMT5 in tumorigenesis including leukemia, lymphoma, and various solid tumors, making PRMT5 an attractive anticancer target.
Our study conclusively demonstrates PRMT5 as a potential target for combination therapy along with these anti-cancer drugs.
PRMT5-mediated arginine methylation of TDP1 for the repair of topoisomerase I covalent complexes. Ishita Rehman, Suparna M Basu, Subhendu K Das, Sangheeta Bhattacharjee, Arijit Ghosh, Yves Pommier* & Benu Brata Das*
* Corresponding authors
Banner image: Dr. Benu Brata Das. Differential expression of DNA repair foci in response to anticancer drug Camptothecin in human Colon cancer cells (HCT116)