Abstract A04: Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP

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Abstract Recently, the inhibition of poly ADP-ribose polymerase, or PARP, in BRCA-mutated cells has been exploited as a therapeutic strategy for cancer due to the strong PARP/BRCA synthetic lethal relationship. Evidence suggests this lethality is likely due to DNA repair defects; however, details of this mechanism remain unclear. To this end, we sought to identify a larger spectrum of genes whose mutation renders cells sensitive to PARP inhibition. Using the model organism Caenorhabditis elegans, we developed an in vivo variomics approach to screen mutated C. elegans strains for sensitivity to the PARP inhibitor olaparib. Multiple sensitive strains contained mutations in either mus-81 or eme-1, two genes that form a heterodimeric DNA endonuclease complex involved in both stalled fork cleavage in replication and Holliday junction resolution in homologous recombination repair. Further investigation revealed that olaparib treatment caused somatic proliferation defects and anaphase bridges in mus-81 mutants. We found the MUS81/PARP genetic interaction from C. elegans to be conserved in human cells. Compared to MUS81 wild-type cell lines, MUS81 knockout cells showed a significant decrease in proliferation after exposure to PARP inhibitor and had characteristics distinct from olaparib-treated BRCA2 knockout cells. Surprisingly, cells that were lacking MUS81 and treated with PARP inhibitor showed a lack of apoptosis, dramatic increase in tetraploidy and higher incidence of anaphase bridges in mitosis. Using cross-species approaches, we have identified a new PARP synthetic lethal interaction that is conserved in human cells. Our results suggest that MUS81 protection after PARP inhibitor treatment is functionally distinct from other homologous recombination repair genes and provides further insights into the mechanism behind PARP inhibitor-induced selective tumor cell killing. Citation Format: Melanie L. Bailey, Nigel J. O’Neil, Philip Hieter. Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A04.