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<em>Saccharomyces cerevisiae</em> Mus81 is a structure-selective endonuclease which constitutes an alternative pathway in parallel with the helicase-topoisomerase Sgs1-Top3-Rmi1 complex to resolve a number of DNA intermediates during DNA replication, repair, and homologous recombination. Previously, it was showed that the N-terminal region of Mus81 was required for its <em>in vivo</em> function in a redundant manner with Sgs1; <em>mus81_Δ120N</em> mutant that lacks the first 120 amino acid residues at the N-terminus exhibited synthetic lethality in combination with the loss of <em>SGS1</em>. In this study, the physiologically important role of the N-terminal region of Mus81 in processing toxic intermediates was further investigated. We examined the cellular defect of <em>sgs1Δmus81_Δ100N</em> cells and observed that although viable, the cells became very sensitive to DNA damaging agents. A single-copy suppressor screening to seek for a factor(s) that could rescue the drug sensitivity of <em>sgs1Δmus81_Δ100N</em> cells was performed and revealed that Flp1, a site-specific recombinase 1 encoded on the 2-micron plasmid was a suppressor. Moreover, Flp1 overexpression could partially suppress the drug sensitivity of <em>mus81Δ</em> cells at 37 °C. Our findings suggest a possible function of Flp1 in coordination with Mus81 and Sgs1 to jointly resolve the branched-DNA structures generated in cells attempting to repair DNA damages.