Fig. 6

A possible model for TOP1cc and DPC repair. TOP1ccs (blue) and other DPCs (grey) represent a block for the replication CMG complex (beige). To remove a TOP1cc, it has to be either degraded by the proteasome or proteases (i.e. SPARTAN) or alternatively displaced/unfolded from DNA. Next, the processed TOP1 can be cleaved by a nuclease, such as MUS81-EME1, SLX1-SLX4, XPF-ERCC1 or MRE11, followed by homologous recombination (HR). DPCs that NER does not remove can also undergo proteolysis by a protease or proteasome, followed by translesion synthesis (TLS). Alternatively, DPCs can be removed by the action of the nucleases and repaired by HR. When a TOP1cc blocks transcription, TOP1 is degraded in a ubiquitin/proteasome 26S-dependent manner. TDP1 then removes the remaining TOP1 peptide and the break is repaired by a single-strand break repair pathway (SSBR)