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Genetic separation of Brca1 functions reveal mutation-dependent Pol theta vulnerabilities

ABSTRACT: Genetic separation of Brca1 functions reveal mutation-dependent Pol theta vulnerabilities

PROVIDER: PRJNA1025027 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26313909_1.fastq.gz	Fastqsanger.gz
	SRR26313909_2.fastq.gz	Fastqsanger.gz
	SRR26313910_1.fastq.gz	Fastqsanger.gz
	SRR26313910_2.fastq.gz	Fastqsanger.gz
	SRR26313911_1.fastq.gz	Fastqsanger.gz

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Genetic separation of Brca1 functions reveal mutation-dependent Pol theta vulnerabilities

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PARG is Essential for Pol-theta-Mediated DNA End-Joining by Removing Repressive Poly-ADP Ribose Marks

Project description:DNA polymerase theta (Pol-theta)-mediated end-joining (TMEJ) repairs DNA double-strand breaks and confers resistance to genotoxic agents. How Pol-theta is regulated at the molecular level to exert TMEJ remains unknown. We find that Pol-theta interacts with and is PARylated by PARP1 in vitro and in cells. PARP1 recruits Pol-theta to the vicinity of DNA damage via PARylation dependent liquid demixing, however, PARylated Pol-theta (PAR-Pol-theta) cannot perform TMEJ due to its inability to bind DNA. PARG-mediated de-PARylation of Pol-theta reactivates its DNA binding and end-joining activities in vitro. Consistent with this, PARG is essential for TMEJ in cells and the temporal recruitment of PARG to DNA damage corresponds with TMEJ activation and dissipation of PARP1 and PAR. These studies support a two-step spatiotemporal mechanism of TMEJ regulation. First, PARP1 PARylates Pol-theta and facilitates its recruitment to DNA damage sites in an inactivated state. PARG subsequently activates TMEJ by removing repressive PAR marks on Pol-theta.

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Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities.

Project description:Homologous recombination (HR)-deficiency induces a dependency on DNA polymerase theta (Polθ/Polq)-mediated end joining, and Polθ inhibitors (Polθi) are in development for cancer therapy. BRCA1 and BRCA2 deficient cells are thought to be synthetic lethal with Polθ, but whether distinct HR gene mutations give rise to equivalent Polθ-dependence, and the events that drive lethality, are unclear. In this study, we utilized mouse models with separate Brca1 functional defects to mechanistically define Brca1-Polθ synthetic lethality. Surprisingly, homozygous Brca1 mutant, Polq-/- cells were viable, but grew slowly and had chromosomal instability. Brca1 mutant cells proficient in DNA end resection were significantly more dependent on Polθ for viability; here, treatment with Polθi elevated RPA foci, which persisted through mitosis. In an isogenic system, BRCA1 null cells were defective, but PALB2 and BRCA2 mutant cells exhibited active resection, and consequently stronger sensitivity to Polθi. Thus, DNA end resection is a critical determinant of Polθi sensitivity in HR-deficient cells, and should be considered when selecting patients for clinical studies.

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Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.

Project description:Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in DNA repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. Cell culture-based studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcriptional regulation and genetic instability. We found that BRCA1 mutation-associated R-loop accumulates preferentially in luminal epithelial cells of cancer-free human breast tissue, and at the 5' end of those genes that experience promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of mouse NELF-B/COBRA1, a Pol II-pausing factor and BRCA1-binding protein, in Brca1 knockout mouse mammary epithelium ameliorates R-loop accumulation and reduces mammary tumorigenesis. Our studies show that Pol II pausing is a previously unappreciated contributor to BRCA1-associated R-loop accumulation and breast cancer development.

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lncRNA SLERT controls phase separation of FC/DFCs to facilitate Pol I transcription

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Phase separation of RNA-binding protein promotes polymerase binding and transcription

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