A proposed model of the SLX4-associated activities during the repair of MMC, CPT, and PARP inhibitor-induced DNA damage. MMC induces DNA ICLs. CPT traps a TOP1 cleavage complex, composed of TOP1 and nicked DNA, and prevents religation of the nicks. Unrepaired nicked DNA can result in reversed forks or turn into DSB when it encounters replication machinery in S phase. Inhibition of PARP prohibits SSB repair. Unrepaired SSB forms DSB during DNA replication, although we speculate that they might also cause reverse forks as seen for the CPT-induced damage. Straight lines and dotted lines represent proposed major and minor activity of the indicated nucleases. XPF-SLX4 complex plays a major role in the ICL repair but is dispensable for repairing CPT and PARP inhibitor-induced DNA lesions. MUS81-SLX4 interaction is critical for conferring resistance to CPT and PARP inhibitor through its activity on stalled/reversed forks, and plays a minor role in ICL repair, possibly during incision or in the homologous recombination step. SLX1-SLX4 resolvase participates in all 3 DNA repair processes, although its function is minor possibly because of existence of parallel/redundant processing pathways.