Autophagic Organelles in DNA Damage Response

Kim, Jeongha; Lee, Sung-Min; Kim, Hyun Woo; Lee, Haksoo; Seong, Ki Moon; Youn, HyeSook; Youn, BuHyun

doi:10.3389/fcell.2021.668735

Cited by 15 publications

(7 citation statements)

References 166 publications

(163 reference statements)

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“…Since our interactomic analysis identified DNA damage/repair, differentiation, and apoptosis as several of the most altered cell functions in IPF MPCs, here we focused on PARP1, CDK1, and BACH1, regulators of DNA damage/repair, cell differentiation and apoptosis signaling, respectively. We demonstrate that IPF MPCs display higher levels of DNA damage and apoptosis, consistence with previous reports demonstrating that increased levels of DNA damage can promote apoptosis [27,34]. It is likely that the increased levels of nuclear PARP1 identified by our quantitative mass spectrometry studies are in response to the increased levels of DNA damage in IPF MPCs.…”

Section: Discussionsupporting

confidence: 90%

Proteomic analysis of the IPF mesenchymal progenitor cell nuclear proteome identifies abnormalities in key nodal proteins that underlie their fibrogenic phenotype

et al. 2022

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IPF is a progressive fibrotic lung disease whose pathogenesis remains incompletely understood. We have previously discovered pathologic mesenchymal progenitor cells (MPCs) in the lungs of IPF patients. IPF MPCs display a distinct transcriptome and create sustained interstitial fibrosis in immune deficient mice. However, the precise pathologic alterations responsible for this fibrotic phenotype remain to be uncovered. Quantitative mass spectrometry and interactomics is a powerful tool that can define protein alterations in specific subcellular compartments that can be implemented to understand disease pathogenesis. We employed quantitative mass spectrometry and interactomics to define protein alterations in the nuclear compartment of IPF MPCs compared to control MPCs. We identified increased nuclear levels of PARP1, CDK1, and BACH1. Interactomics implicated PARP1, CDK1, and BACH1 as key hub proteins in the DNA damage/repair, differentiation, and apoptosis signaling pathways respectively. Loss of function and inhibitor studies demonstrated important roles for PARP1 in DNA damage/repair, CDK1 in regulating IPF MPC stemness and self‐renewal, and BACH1 in regulating IPF MPC viability. Our quantitative mass spectrometry studies combined with interactomic analysis uncovered key roles for nuclear PARP1, CDK1, and BACH1 in regulating IPF MPC fibrogenicity.

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Section: Discussionsupporting

confidence: 90%

Proteomic analysis of the IPF mesenchymal progenitor cell nuclear proteome identifies abnormalities in key nodal proteins that underlie their fibrogenic phenotype

et al. 2022

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“…Autophagy is one of the factors determining radiosensitivity [ 11 ]. LC3-II levels were increased in HLF and HuH6 cells after 5-Gy irradiation.…”

Section: Resultsmentioning

confidence: 99%

NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP

Sakaguchi

Tsuchiya

Kitagawa

et al. 2022

IJMS

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A long noncoding RNA (lncRNA), nuclear enriched abundant transcript 1 (NEAT1) variant 1 (NEAT1v1), is involved in the maintenance of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). CSCs are suggested to play important roles in therapeutic resistance. Therefore, we investigated whether NEAT1v1 is involved in the sensitivity to radiation therapy in HCC. Gene knockdown was performed using short hairpin RNAs, and NEAT1v1-overexpressing HCC cell lines were generated by stable transfection with a NEAT1v1-expressing plasmid DNA. Cells were irradiated using an X-ray generator. We found that NEAT1 knockdown enhanced the radiosensitivity of HCC cell lines and concomitantly inhibited autophagy. NEAT1v1 overexpression enhanced autophagy in the irradiated cells and conferred radioresistance. Gamma-aminobutyric acid receptor-associated protein (GABARAP) expression was downregulated by NEAT1 knockdown, whereas it was upregulated in NEAT1v1-overexpressing cells. Moreover, GABARAP was required for NEAT1v1-induced autophagy and radioresistance as its knockdown significantly inhibited autophagy and sensitized the cells to radiation. Since GABARAP is a crucial protein for the autophagosome-lysosome fusion, our results suggest that NEAT1v1 confers radioresistance to HCC by promoting autophagy through GABARAP.

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“…Accordingly, whether autophagy should be inhibited or induced in GBM treatment is unclear. As autophagy is a self-clearance pathway that maintains basal reactive oxygen species (ROS) levels by removing the dysfunctional organelles and oxidized peroxisomes, it can protect cells from chemotherapeutic agent-induced ROS [ 54 ]. Autophagy induction may contribute to maintaining the stemness characteristics of GSCs [ 55 ].…”

Section: Mechanisms Of Chemoresistance In Gscsmentioning

confidence: 99%

Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies

et al. 2022

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Glioblastoma (GBM) is the most malignant primary brain tumor. The current standard approach in GBM is surgery, followed by treatment with radiation and temozolomide (TMZ); however, GBM is highly resistant to current therapies, and the standard of care has not been revised over the last two decades, indicating an unmet need for new therapies. GBM stem cells (GSCs) are a major cause of chemoresistance due to their ability to confer heterogeneity and tumorigenic capacity. To improve patient outcomes and survival, it is necessary to understand the properties and mechanisms underlying GSC chemoresistance. In this review, we describe the current knowledge on various resistance mechanisms of GBM to therapeutic agents, with a special focus on TMZ, and summarize the recent findings on the intrinsic and extrinsic mechanisms of chemoresistance in GSCs. We also discuss novel therapeutic strategies, including molecular targeting, autophagy inhibition, oncolytic viral therapy, drug repositioning, and targeting of GSC niches, to eliminate GSCs, from basic research findings to ongoing clinical trials. Although the development of effective therapies for GBM is still challenging, this review provides a better understanding of GSCs and offers future directions for successful GBM therapy.

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Autophagic Organelles in DNA Damage Response

Cited by 15 publications

References 166 publications

Proteomic analysis of the IPF mesenchymal progenitor cell nuclear proteome identifies abnormalities in key nodal proteins that underlie their fibrogenic phenotype

Proteomic analysis of the IPF mesenchymal progenitor cell nuclear proteome identifies abnormalities in key nodal proteins that underlie their fibrogenic phenotype

NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP

Targeting Glioblastoma Stem Cells to Overcome Chemoresistance: An Overview of Current Therapeutic Strategies

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