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ABSTRACT: Variants in DNA damage response mutant

PROVIDER: PRJNA541046 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR9009240.fastq.gz	Fastqsanger.gz
	SRR9009280.fastq.gz	Fastqsanger.gz
	SRR9009460.fastq.gz	Fastqsanger.gz
	SRR9009490.fastq.gz	Fastqsanger.gz

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Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Project description:Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the liver, brain, kidney and retina. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3’-5’ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of the radiation injury, we reasoned that nuclear TREX1 promotes DNA damage. Here, we show that RVCL-associated TREX1 variants cause DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a new mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

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Project description:Functional interrogation of DNA damage response variants with base editing screens

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A metabolic map of the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis

Project description:Targetted metabolomics in U2OS PRDX1 WT and PRDX1-/- While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential when cells are exposed to DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species levels. Moreover, PRDX1 controls aspartate availability, which is required for the DNA damage repair-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of γΗ2ΑΧ nuclear foci, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.

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Project description:DNA damage response in seeds

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Project description:DNA damage response in Fusarium.

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Project description:DNA damage response in Arabidopsis

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Critical residues in the Ku70 von Willebrand A domain mediate Ku interaction with the LigIV-XRCC4 complex in non-homologous end-joining

Project description:Interrogated the Ku interactome in response to DNA damage with wildtype and mutant Ku70

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Project description:Upon DNA damage, numerous proteins are targeted for ubiquitin-dependent proteasomal degradation. We show that phosphorylation of Rpn10/PSMD4 (ubiquitin receptor of the proteasome) at Ser266, is required for DNA repair. Here, we performed TurboID proximity labeling for capturing the proteasome substrates under DNA damage. Numerous proteins which involve in DNA damage response, chromosome reorganization cell cycle and histone modification were identified as the potential pronuteasome substrates. We find that DNA damage reduced the overall affinity between substrates and wild-type Rpn10 compared to Rpn10-Ser266 mutant cells. Combining TMT quantitative proteomic studies, we observed the dynamics of more than 2,000 nuclear proteins upon DNA damage and time course release. Most proteins were accumulated in wild-type cells in the time course release, while the Rpn10-Ser266 mutant cells show almost no changes in protein level. These findings reveal an inherent self-limiting mechanism of the proteasome that, by controlling substrate recognition through Rpn10 phosphorylation, fine-tunes protein degradation for optimal responses under stress.

2023-11-28 | PXD047298 |

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