DNA-protein crosslinks (DPCs) are formed in the course of normal cell metabolism. However, their prolonged persistence can be extremely toxic, cause genome instability and promote diseases such as cancer.
The Stutz laboratory, together with the Kornmann (University of Oxford) and Loewith groups,describes a new mechanism required for the efficient DPC disassembly. Through a yeast genetic screen, Serbyn and collaborators identified the enigmatic Ddi1 protease as a new candidate degrading the protein moiety of DPCs. The authors show that Ddi1 helps to resolve a broad variety of DNA-protein crosslinks and functions independently of the known pathways involved in proteolytic DPC elimination.
Loss of Ddi1 sensitizes cells to several compounds that trap DPCs, including approved anti-cancer drugs. The latter provides novel insights into the putative mechanisms of drug resistance often observed in therapeutics.
The study was published in Molecular Cell on January 2, 2020.