Genetic suppressor elements (GSEs) are cDNA fragments encoding either truncated proteins, acting as dominant-negative mutants, or inhibitory antisense RNA segments counteracting with the gene from which they are derived. To identify genes controlling the cell response to cytotoxic agents, a normalized retroviral library of randomly fragmented cDNAs from Chinese hamster cell line DC-3F was screened for GSEs conferring resistance to the topoisomerase II inhibitor 9-OH-ellipticine. From 218 cDNA fragments isolated, 11 functional GSEs, corresponding to at least 8 independent genes, were selected. The gene corresponding to the most abundant GSE encodes two proteins, p77 and p82, highly homologous to proteins detected in various species and carrying the sequence motifs characteristic of the protein arginine N-methyltransferase family. Furthermore, a methylase activity was observed on myelin basic protein in immunoprecipitates of hemagglutinin-tagged p77 and p82. Therefore, p77 and p82 are the first identified members of a new protein arginine N-methyltransferase family. A decreased expression of these enzymes is associated with either resistance or hypersensitivity to a broad range of DNA-damaging agents. Our data indicate that down-regulation of these enzymes in the GSE-expressing cells would alter one or several steps downstream of the drug-target interaction in the drug-response pathway.