03 February 2023
Fixing abortive DNA cleavage
Published online 15 March 2010
Topoisomerases play an integral role in human cells through cleavage of DNA strands. However, certain topoisomerase poisons can lead to failure of the action of the enzymes, linking them to the broken DNA strands by two different types of bond: 3'-phosphotyrosyl and 5'-phosphotyrosyl. This can cause hereditary diseases and cancers in humans. The enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) that is present in the body breaks 3'-phosphotyrosyl bonds, which are caused by topoisomerase I, thereby liberating the DNA. No known enzyme acted on the other type of bond.
However, a recent paper co-authored by Sherif El Khamisy from Ain Shams University in Egypt documented for the first time an enzyme, TTRAP, which breaks 5'-phosphotyrosyl bonds that are caused by topoisomerase II. Extracts of human whole cells showed that the newly discovered enzyme was the main source of 5'-tyrosyl DNA phosphodiesterase activity. In vivo, an increase in the concentration of the enzyme in cells led to higher resistance to topoisomerase II poisons.
The researchers suggest that TTRAP should be named tyrosyl DNA phosphodiesterase-2 (TDP2), as it has a complementary action to that of TDP1. Together, these enzymes offer the cell the ability to liberate DNA from topoisomerases. Further investigations are needed to understand the role that the new enzyme plays in other fields of cell biology. This discovery might have important implications for the treatment of cancer and other neurological disorders.