A number of DNA repair nucleases have the domain ERCC4 (IPR006166), such as Rad1, XPF, and the cross-linking endonucleases EME1 and Mus81. The XPF/Rad1/Mus81-dependent nuclease family plays a crucial role in maintaining genomic stability by precisely cleaving branched structures generated during DNA repair, replication, and recombination. The architecture of the nuclease domain is strikingly similar to that of restriction endonucleases.