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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice

ABSTRACT: The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice

PROVIDER: PRJNA647336 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12267200.fastq.gz	Fastqsanger.gz
	SRR12267201.fastq.gz	Fastqsanger.gz
	SRR12267202.fastq.gz	Fastqsanger.gz
	SRR12267203.fastq.gz	Fastqsanger.gz
	SRR12267204.fastq.gz	Fastqsanger.gz

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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [ChIP-Seq]

Project description: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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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [CRISPR-Cas9 screen]

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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [ChIP-Seq]

Project description:The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [ChIP-Seq]

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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [CRISPR-Cas9 screen]

Project description:The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [CRISPR-Cas9 screen]

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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [Nascent RNA-seq]

Project description:The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [Nascent RNA-seq]

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The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice

Project description:This SuperSeries is composed of the SubSeries listed below.

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THAP1 is cell type dependent regulator of SP1 family crucial for dystonic syndromes in human and rat [Striatum_RNA-seq]

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