Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway

Dubreuil, Michael M.; Morgens, David W.; Okumoto, Kanji; Honsho, Masanori; Contrepois, Kévin; Lee‐McMullen, Brittany; Traber, Gavin M.; Sood, Ria S.; Dixon, Scott J.; Snyder, M; Fujiki, Yukio; Bassik, Michael C.

doi:10.1016/j.celrep.2020.01.013

Cited by 52 publications

(51 citation statements)

References 146 publications

(174 reference statements)

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“…A total of 625 gRNAs were found to be significantly enriched and 345 gRNAs depleted in HEK293 cells after H 2 O 2 treatment as compared to the cells without H 2 O 2 treatment (Supplementary Table S1). Interestingly, several of these targets were previously identified in HeLa cells with H 2 O 2 treatment [18], such as EPT1, UGT1A6, LIG3, and PEX11A ( Fig. 1D, E).…”

Section: Genome-wide Crispr Screening Identified An Oxidative Stressmentioning

confidence: 76%

“…The gRNA sequences in the selected cells were analyzed by next-generation sequencing (NGS). The data were analyzed by casTLE [17,18]. A total of 625 gRNAs were found to be significantly enriched and 345 gRNAs depleted in HEK293 cells after H 2 O 2 treatment as compared to the cells without H 2 O 2 treatment (Supplementary Table S1).…”

Section: Genome-wide Crispr Screening Identified An Oxidative Stressmentioning

confidence: 99%

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Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth

Zhao

Lau

et al. 2020

Oncogene

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Colorectal cancer is the third leading cause of cancer-related deaths in the United States and the third most common cancer in men and women. Around 20% colon cancer cases are closely linked with colitis. Both environmental and genetic factors are thought to contribute to colon inflammation and tumor development. However, the genetic factors regulating colitis and colon tumorigenesis remain elusive. Since reactive oxygen species (ROS) is vitally involved in tissue inflammation and tumorigenesis, here we employed a genome-wide CRISPR knockout screening approach to systemically identify the genetic factors involved in the regulation of oxidative stress. Next generation sequencing (NGS) showed that over 600 gRNAs including the ones targeting LGALS2 were highly enriched in cells survived after sublethal H2O2 challenge. LGALS2 encodes the glycan-binding protein Galectin 2 (Gal2), which is predominantly expressed in the gastrointestinal tract and downregulated in human colon tumors. To examine the role of Gal2 in colitis, we employed the dextran sodium sulfate (DSS)-induced acute colitis model in mice with (WT) or without Lgals2 (Gal2-KO) and showed that Gal2 deficiency ameliorated DSS-induced colitis. We further demonstrated that Gal2-KO mice developed significantly larger tumors than WT mice using Azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal cancer model. We found that STAT3 phosphorylation was significantly increased in Gal2-deficient tumors as compared to those in WT mice. Gal2 overexpression decreased the proliferation of human colon tumor epithelial cells and blunted H2O2-induced STAT3 phosphorylation. Overall, our results demonstrate that Gal2 plays a suppressive role in colon tumor growth and highlights the therapeutic potential of Gal2 in colon cancer.

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Section: Genome-wide Crispr Screening Identified An Oxidative Stressmentioning

confidence: 76%

Section: Genome-wide Crispr Screening Identified An Oxidative Stressmentioning

confidence: 99%

Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth

Zhao

Lau

et al. 2020

Oncogene

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“…Compared to other recent genetic screens focusing on oxidative stress toxicity in human cells 105,106 , our screens are unique in the following aspects. First, we used post-mitotic neurons instead of cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Tian

Abarientos

Hong

et al. 2020

Preprint

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SUMMARYSingle-cell transcriptomics provide a systematic map of gene expression in different human cell types. The next challenge is to systematically understand cell-type specific gene function. The integration of CRISPR-based functional genomics and stem cell technology enables the scalable interrogation of gene function in differentiated human cells. Here, we present the first genome-wide CRISPR interference and CRISPR activation screens in human neurons.We uncover pathways controlling neuronal response to chronic oxidative stress, which is implicated in neurodegenerative diseases. Unexpectedly, knockdown of the lysosomal protein prosaposin strongly sensitizes neurons, but not other cell types, to oxidative stress by triggering the formation of lipofuscin, a hallmark of aging, which traps iron, generating reactive oxygen species and triggering ferroptosis. We also determine transcriptomic changes in neurons following perturbation of genes linked to neurodegenerative diseases. To enable the systematic comparison of gene function across different human cell types, we establish a data commons named CRISPRbrain.

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“…Phosphogluconate dehydrogenase (PGD) depletion leads to accumulation of the upstream metabolite 6-phosphogluconate (6PG), which inhibits glycolysis. Therefore, glucose flux through the PPP is increased and this metabolic rewiring enhances NADPH production [32]. The synthesis of NADPH also depends on NAD + production, since it is utilized to synthesize NADP + .…”

Section: Metabolism Functions In the Antioxidant Responsementioning

confidence: 99%

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

Moretton

Loizou

2020

Cancers

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Metabolism is a fundamental cellular process that can become harmful for cells by leading to DNA damage, for instance by an increase in oxidative stress or through the generation of toxic byproducts. To deal with such insults, cells have evolved sophisticated DNA damage response (DDR) pathways that allow for the maintenance of genome integrity. Recent years have seen remarkable progress in our understanding of the diverse DDR mechanisms, and, through such work, it has emerged that cellular metabolic regulation not only generates DNA damage but also impacts on DNA repair. Cancer cells show an alteration of the DDR coupled with modifications in cellular metabolism, further emphasizing links between these two fundamental processes. Taken together, these compelling findings indicate that metabolic enzymes and metabolites represent a key group of factors within the DDR. Here, we will compile the current knowledge on the dynamic interplay between metabolic factors and the DDR, with a specific focus on cancer. We will also discuss how recently developed high-throughput technologies allow for the identification of novel crosstalk between the DDR and metabolism, which is of crucial importance to better design efficient cancer treatments.

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Systematic Identification of Regulators of Oxidative Stress Reveals Non-canonical Roles for Peroxisomal Import and the Pentose Phosphate Pathway

Cited by 52 publications

References 146 publications

Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth

Genome-wide CRISPR screen identifies LGALS2 as an oxidative stress-responsive gene with an inhibitory function on colon tumor growth

Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis

Interplay between Cellular Metabolism and the DNA Damage Response in Cancer

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