biostudies-literatureBlandino FAssociazione Italiana per la Ricerca sul CancroItalian Ministry of Health6723-6737https://www.ebi.ac.uk/biostudies/studies/S-EPMC10359636biostudies-literatureUnknown51(13)The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M- or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear. Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of a constitutively-active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicate that deregulated actioNucleic acids researchPhosphorylation status of MUS81 is a modifier of Olaparib sensitivity in BRCA2-deficient cells.PMC1035963619971RF-2016-0236202221428Noto AFiglioli CPichierri PPugliese GMMalacaria EFranchitto ABlandino FfalsePhosphorylation status of MUS81 is a modifier of Olaparib sensitivity in BRCA2-deficient cells.The MUS81 complex is crucial for preserving genome stability through resolution of branched DNA intermediates in mitosis and also for the processing of deprotected replication forks in BRCA2-deficient cells. Because of the existence of two different MUS81 complexes in mammalian cells that act in M- or S-phase, whether and how the PARPi sensitivity of BRCA2-deficient cells is affected by loss of MUS81 function is unclear. Here, using a mutant of MUS81 that impairs its function in M-phase, we show that viability of BRCA2-deficient cells but not their PARPi sensitivity requires a fully-functional MUS81 complex in mitosis. In contrast, expression of a constitutively-active MUS81 is sufficient to confer PARPi resistance. From a mechanistic point of view, our data indicate that deregulated actio2023-01-01T00:00:00Z2023 Jul2025-07-02T03:04:38.228Z2025-07-02T03:04:38.228ZS-EPMC103596363725481010.1093/nar/gkad470