The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice

Abstract

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 PARPi 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.

A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding

“…In prior studies, we and others (4, 10) have identified several transcription factors and epigenetic modifiers that are significantly coenriched with THAP1 on the genome. Most prominent among them are YY1 and HCFC1 (Figure 3E), proteins that interact with THAP1 (4, 24, 25) and co-regulate THAP1-bound genes (4,26).…”

YY1: A New Gene for Childhood Onset Dystonia with Prominent Oromandibular‐Laryngeal Involvement?

“…7 Direct YY1/THAP1 interaction has been demonstrated 7 and an YY1/THAP1 co-regulatory model impairing DNA double-stranded break repair has been suggested as a pathomechanism for THAP1-associated dystonia. 8 Additionally, both YY1 and THAP1 play key roles in oligodendrocyte maturation, 7 perhaps relevant to white matter abnormalities on MRI in YY1 patients 1 and microstructural white matter abnormalities on diffusion tensor imaging in THAP1 patients. 9,10 Although speculative at present, these overlapping functions and localizations may provide clues to pathogenesis.…”