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| Status |
Public on Apr 13, 2021 |
| Title |
The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [Nascent RNA-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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. 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 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.
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| Overall design |
Nascent RNA-seq data to study gene expression profiles of Thap1-/- MEFs
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| Contributor(s) |
Shinoda K, Zong D, Callen E, Wu W, Dumitrache LC, Belinky F, Wong N, Ishikawa M, Stanlie A, Ehrlich ME, McKinnon PJ, Nussenzweig A |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Jul 20, 2020 |
| Last update date |
Apr 16, 2021 |
| Contact name |
Wei Wu |
| Organization name |
National Cancer Institute
|
| Department |
Center for Cancer Research
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| Lab |
Laboratory of Genome Integrity
|
| Street address |
9000 Rockville Pike
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
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| Samples (14)
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| This SubSeries is part of SuperSeries: |
| GSE154729 |
The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice |
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| Relations |
| BioProject |
PRJNA647339 |
| SRA |
SRP272579 |
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