Autophagy (self-eating) is a critical cell process that allows cells to degrade and cycle damaged cell components. In this case, TEX264 is key to identifying and recycling DNA with a permanent chemical link to a protein.
Covalent attachment of proteins to DNA is a constant problem. Unless cells can clear their DNA of attached proteins they would die, so we knew they could do this, we just didn’t know how.
Kristijan Ramadan’s group has uncovered how cells handle one example of this, the formation of a permanent link between DNA and a protein called Topoisomerase 1 to give a Topoisomerase 1 -cleavage complex (Top1-ccs). Topoisomerase 1 (Top-1) is usually involved in unwinding DNA strands so that they may be easily copied, but if Top-1 gets permanently linked to DNA copying would get stuck and the cell would suffer further DNA damage.
Specialised DNA repair machinery composed of the p97 ATPase, SPRTN protease and an autophagy receptor TEX264, tackles the linked protein-DNA. Inactivation of the p97-SPRTN-TEX264 complex leads to accumulation of Top1-ccs and genomic instability. Pathological accumulation of Top1-ccs is linked to neurodegeneration and cancer.
The discovery of TEX264 and role it plays in resolving problems associated with covalent linking of proteins to DNA is important for cancer therapy, as Topoisomerase 1 inhibitors are one of the commonly used chemotherapeutics and they kill cancer cells by accumulation of Top1-ccs. Kristijan Ramadan’s report could be vital in treating tumours which have become resistant to Topoisomerase 1 inhibitors.
Full article available here: https://www.nature.com/articles/s41467-020-15000-w