Several environmental agents and intracellular metabolites promote formation of a covalent bond between protein and DNA, thus stabilising one of the most toxic DNA lesions – a DNA-protein crosslink (DPC). Bulky in their nature, DPCs prevent genuine progression of the replication and transcription machineries, thus seriously threatening DNA integrity. This work reveals two novel pathways contributing to cell survival in the presence of toxic DPC lesions: the SUMO posttranslational modification and the aspartic protease Ddi1. SUMOylation is described here to regulate the outcomes of toxic Top1-DNA trapping or formation of chemically identical covalent DPC lesions. Ddi1 is required for the efficient elimination Top1-DNA and other DPC adducts in a protease dependent manner, and is therefore proposed to act as a novel dedicated proteolytic enzyme contributing to DPC disassembly. In summary, the manuscript presents novel insights into the molecular mechanisms underlying the cellular response to toxic DPC lesions.