The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice. Shinoda et al

Published: 06-04-2021| Version 1 | DOI: 10.17632/35jfgtzkk4.1
Kenta Shinoda,
Dali Zong,
Elsa Callen,
Wei Wu,
Lavinia Dumitrache,
Frida Belinky,
Raj Chari,
Nancy Wong,
Momoko Ishikawa,
Andre Stanlie,
Trisha Multhaupt-Buell,
Nutan Sharma,
Laurie Ozelius,
Michelle Ehrlich,
Peter McKinnon,
Andre Nussenzweig


The Shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and REV7, shields double strand DNA 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. Consistently, we show that embryonic lethality and PARPi sensitivity of BRCA1 deficient mice is rescued by ablation of SHLD1. In contrast, loss of THAP1 in BRCA2 deficient cells increases genome instability and correlates with improved responses to chemotherapy. In summary, our study provides the first example of a transcriptional network that directly controls DSB repair choice and a potential link between pathogenic THAP1 mutations, found in patients with the neurodevelopmental movement disorder adult-onset torsion dystonia type 6 (DYT6), and DNA damage.