DNA Damage Caused by Cancer Treatment Reversed by ZATT Protein

Source: National Institutes of Health (NIH)

Summary: An international team of researchers discovered that cells can fix the DNA damage caused by cancer treatment by proteins called ZATT and TDP2.

Individuals suffering from cancer may receive some type of cancer treatments, during the treatment there is a type of dangerous DNA damage is observed. This type of DNA damage is termed as DNA-Protein Crosslink (DPC). An international team of researchers at the National Institutes of Health discovered for the first time that cells fix the DNA damage by eliminating the DPCs with the help of SUMO ligase ZATT (ZNF451) and TDP2 (tyrosyl-DNA phosphodiesterase2) proteins. Understanding the mechanism how ZATT and TDP2 proteins work together to repair the DNA damage may help to improve the health outcomes of patients suffering from cancer. The study was published in the journal Science.

DNA-Protein Crosslink

Illustration of a TOP2 DNA-protein cross-link (magenta) bound to DNA. Credit: Scott Williams

DPCs are formed when the cellular proteins are covalently trapped on DNA strands when they are exposed to different chemotherapeutic drugs, activated carcinogens and environmental chemicals. When DNA is entangled like a ball yarn inside the cells, organisms use topoisomerase 2 (TOP2) to cut and retie (untangle) individual threads of DNA ball. In this situation, stable DPC-TOP2 complexes are formed and they are like double-edged swords and have to be removed or else they trigger cell death. Researchers said that it was necessary to learn about DPCs location and how they are broken as DPC-TOP2 lesions can be the source of disease as they may be responsible the for the rearrangement of the organism’s genome that leads to cancer.

Williams said, “In this study, we discovered a new molecular disarmament apparatus for these cell-killing bombs, ZATT is like a bomb-sniffing dog, so when it locates its target, it sounds an alarm to mobilize the recruitment of TDP2, which cuts the red wire to disarm these threats.”

Schellenberg said, “We’ve discovered how we defend against this potent means of cell killing, it is our hope that this information will enable development of new drugs that target these defenses. By lowering the defenses, we may make drugs that kill cancer cells more effective.”

More Information: M.J. Schellenberg et al, “ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links” Science (2017). DOI: 10.1126/science.aam6468

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