Multi-task protein repairs damaged DNA and helps fight cancer
The intracellular protein Tdp2, known for its anti-inflammatory properties and its role in repositioning of cells in the embryonic development phase, now also appears to play a crucial role in restoring damaged DNA. The discovery opens new avenues for fighting cancer. It was the result of collaborative research by embryologist and stem cell researcher Danny Huylebroeck (KU Leuven) and DNA repair specialist Keith Caldecott (University of Sussex).
Tdp2 was first identified as an anti-inflammatory protein by Huylebroeck and his team in 2000. In 2007, after studying the protein in zebrafish embryos, the team reported that Tdp2 also plays a role in cell behaviour in the earliest stage of development, when cells begin to locate to specific cell populations that eventually participate in the formation of organs.
But these two mechanisms are governed by only one part of the protein, which begs the question: what does the rest of the protein do? Researchers hypothesized that the mystery protein fragment may play a role in DNA repair because its structure is similar to a number of other known proteins responsible for DNA repair. Repair proteins are crucial because our cells naturally accumulate errors in the DNA and these must be corrected to ensure cell survival and healthy tissue growth. Even healthy cells sometimes require DNA repair.
The researchers succeeded in deactivating the two copies of the Tdp2 gene in mouse models so that the mice no longer produced the protein. This allowed the researchers to examine its implications for DNA repair. Huylebroeck: "My British colleague Keith Caldecott, working with the cells of Leuven-bred Tdp2-deficient mice, showed that Tdp2 was a DNA repair protein that worked in a different way than other such proteins and was exceptionally precise in repairing DNA damage. There are various mechanisms for repairing DNA. One is provoked by topoisomerase-2 (Top2), a protein that helps disentangle DNA's double helix. Top2 cleaves the DNA and disappears from it once the cut in the DNA is repaired by Tdp2. In the mice that lacked Tdp2, however, Top2 remained trapped on the DNA, leaving the cut unrepaired. This can be very detrimental to the cell, particularly if there is another cut nearby, leading to a double-stranded DNA break. It can also cause cancer."
The discovery of Tdp2’s repair mechanism opens at least two new avenues for fighting cancer, says Huylebroeck: "We could think of increasing the amount of Tdp2 in healthy cells; we could also try to reduce its level or activity in tumours so the repair mechanism remains blocked in tumours, leaving the cells unrepaired. This strategy is already used in cancer therapies: the cancer cell-killing drug etoposide, for instance, traps Top2 on DNA to kill cancer cells. Unfortunately, etoposide also increases DNA cleaving in healthy cells, which increases the likelihood that new cancers will arise from healthy cells after treatment of tumour cells with etoposide. This side effect could now be countered with a higher dose of Tpd2." Future research will also explore the role of Tdp2 in stabilising or repairing the genome of neurons in the brain.
Click here for the full text of the study “TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo' in PLOS Genetics.