TY - JOUR T1 - The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice JF - bioRxiv DO - 10.1101/2020.07.19.210773 SP - 2020.07.19.210773 AU - Kenta Shinoda AU - Dali Zong AU - Elsa Callen AU - Wei Wu AU - Lavinia C. Dumitrache AU - Frida Belinky AU - Nancy Wong AU - Momoko Ishikawa AU - Andre Stanlie AU - Michelle Ehrlich AU - Peter J. McKinnon AU - Andre Nussenzweig Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/19/2020.07.19.210773.abstract N2 - The Shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and REV7, shields DNA double strand breaks (DSBs) from nucleolytic resection. The end-protecting activity of Shieldin promotes productive non-homologous end joining (NHEJ) in G1 but can threaten genome integrity during S-phase by blocking homologous recombination (HR). Curiously, the penultimate Shieldin component, SHLD1 is one of the least abundant mammalian proteins. Here, we report that the transcription factors THAP1, YY1 and HCF1 bind directly to the SHLD1 promoter, where they cooperatively maintain the low basal expression of SHLD1. Functionally, this transcriptional network ensures that SHLD1 protein levels are kept in check to enable a proper balance between end protection and end resection during physiological DSB repair. In the context of BRCA1 deficiency, loss of THAP1 dependent SHLD1 expression confers cross resistance to PARP inhibitor and cisplatin, and shorter progression free survival in ovarian cancer patients. In contrast, loss of THAP1 in BRCA2 deficient cells increases genome instability and correlates with improved responses to chemotherapy. Pathogenic THAP1 mutations are causatively linked to the adult-onset torsion dystonia type 6 (DYT6) movement disorder, but the critical disease targets are unknown. We further demonstrate that murine models of Thap1-associated dystonia show reduced Shld1 expression concomitant with elevated levels of unresolved DNA damage in the brain. In summary, our study provides the first example of a transcriptional network that directly controls DSB repair choice and reveals a previously unsuspected link between DNA damage and dystonia.Competing Interest StatementThe authors have declared no competing interest. ER -