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 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..

BRCA1: a key player at multiple stages of homologous recombination in DNA double-strand break repair

“…On the contrary, inactivating Shieldin complex by Shld1 KO or Shld2 KO lifts the block on both DNA end resection and RNF168-mediated PALB2 loading. Therefore, Shld1 KO or Shld2 KO rescues embryonic lethality of Brca1 Δ11/Δ11 mice and no obvious abnormalities are reported for Brca1 Δ11/Δ11 ;Shld1 −/− or Brca1 Δ11/Δ11 ;Shld2 −/− mice, suggesting that HR is likely restored (Ling et al, 2020;Shinoda et al, 2021). In line with these observations, Rnf168 KO rescues both embryonic lethality and HR of Brca1 Δ2/Δ2 mice, which produce BRCA1ΔRING protein that efficiently interacts with PALB2 (Zong et al, 2019).…”

SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

“…Epistasis between 53BP1-RIF1 and the SHLD complex is remarkable in multiple NHEJ reactions, including CSR, the fusion of telomeres lacking TRF2, and the repair of DSBs in BRCA1-deficient cells treated with PARP inhibitors [23][24][25] . In AID-inducible B cell lines, loss of any of the SHLD complex components similarly impairs CSR that is associated with enhanced DSB end resection and the accumulation of chromosomal breaks at immunoglobulin switching sites [26][27][28][29][30][31][32][33][34] . In mice, loss of REV7 or SHLD2 does not impact lymphocyte development while severely compromising CSR 27,30 .…”

Ying Yang 1 engagement in brain pathology

“…Intriguingly, several studies have demonstrated that THAP1 frequently co‐occupies its target genes with the transcriptional co‐regulators YY1 and HCFC1 (Mazars et al, 2010; Michaud et al, 2013; Shinoda et al, 2021; Yellajoshyula et al, 2017), which are recruited to the promoters by THAP1 (Hollstein et al, 2017; Yellajoshyula et al, 2017). Nevertheless, the interest in YY1 in the context of dystonia is quite a new issue and there is certainly much more to be explained.…”