Exploring the endonuclease MUS81 as a new factor impacting on cancer chemosensitivity

The MUS81 complex is a crucial factor for genome stability maintenance and has been proposed as cancer predisposition gene 1,2. The complex is regulated by Casein Kinase 2 (CK2) through phosphorylation at serine 87 (S87), which is essential for resolving branched intermediates during mitosis 3. Our previous findings show that the phosphomimetic S87D-MUS81 mutant confers PARP inhibitor (PARPi) resistance in BRCA2-deficient backgrounds 4, possibly because replication-related double-strand breaks (DSBs) can be completely resolved through alternative end-joining (Alt-EJ) 5. Thus, deregulated function of MUS81 emerged as a potential modifier of the response to PARPi when BRCA2 is mutated or absent. In this study, we investigate why the S87D-MUS81 mutant aberrantly targets DNA replication forks. We found that S87D-MUS81 is hyper-recruited at ongoing replication forks and that the characteristic phenotype of S87D-MUS81 mutant cells is reversed by depletion of the protein scaffold SLX4 by siRNA transfection. This indicates that the unscheduled cleavage function conferred to MUS81 by the S87D mutation and excessive recruitment at DNA replication forks depend on SLX4. We confirm these findings also using a set of mutations that abrogate the binding of MUS81 to SLX4. These findings could lead to a better understanding of the relationship between MUS81 status, PARPi chemosensitivity and a possible MUS81 exploitation in target therapy.