Discovering how cells repair lethal DNA-protein crosslinks
Cell-killing DNA-protein crosslinks occur when cellular proteins become stuck to DNA strands. One such protein, called topoisomerase 2 (TOP2), forms crosslinks with DNA upon exposure to certain widely used anticancer drugs, environmental toxicants, chemical metabolites, tobacco, and ultraviolet light. Cells have developed mechanisms to repair DNA-protein crosslinks, but the precise mechanism by which they do so has remained mysterious.
IRP researchers led by Scott Williams, Ph.D., discovered the ZATT-TDP2 complex, a set of molecules that work together to fix TOP2 DNA-protein crosslinks.
Certain chemotherapies kill cancer cells by inducing TOP2 DNA-protein crosslinks, and the investigators theorize that the newly discovered ZATT-TDP2 complex underlies the process by which tumors become resistant to these treatments. This information may enable the development of new drugs that improve cancer treatments by targeting those cellular defenses.
Schellenberg MJ, Lieberman JA, Herrero-Ruiz A, Butler LR, Williams JG, Munoz-Cabello AM, Mueller GA, London RE, Cortes-Ledesma F, Williams RS. (2017). ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. Science. Sept 29;357(6358):1412-1416.