Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity

Anand, Sumit Kumar; Sharma, Ankita; Singh, Neha; Kakkar, Poonam

doi:10.1016/j.dnarep.2019.102748

Cited by 70 publications

(38 citation statements)

References 160 publications

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“…Knockdown of Parkin reversed the promoting effect of BMSCs on mitophagy. SIRT1 is a primary regulator directing the stress response to mitophagy (44). Elevated SIRT1 increases Parkin expression, thus leading to the activation of mitophagy (45).…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Sepsis-Induced Acute Kidney Injury by Promoting Mitophagy of Renal Tubular Epithelial Cells via the SIRT1/Parkin Axis

2021

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Sepsis is a common risk factor for acute kidney injury (AKI). Bone marrow-derived mesenchymal stem cells (BMSCs) bear multi-directional differentiation potential. This study explored the role of BMSCs in sepsis-induced AKI (SI-AKI). A rat model of SI-AKI was established through cecal ligation and perforation. The SI-AKI rats were injected with CM-DiL-labeled BMSCs, followed by evaluation of pathological injury of kidney tissues and kidney injury-related indicators and inflammatory factors. HK-2 cells were treated with lipopolysaccharide (LPS) to establish SI-SKI model in vitro. Levels of mitochondrial proteins, autophagy-related proteins, NLRP3 inflammasome-related protein, and expressions of Parkin and SIRT1 in renal tubular epithelial cells (RTECs) of kidney tissues and HK-2 cells were detected. The results showed that BMSCs could reach rat kidney tissues and alleviate pathological injury of SI-SKI rats. BMSCs inhibited inflammation and promoted mitophagy of RTECs and HK-2 cells in rats with SI-AKI. BMSCs upregulated expressions of Parkin and SIRT1 in HK-2 cells. Parkin silencing or SIRT1 inhibitor reversed the promoting effect of BMSCs on mitophagy. BMSCs inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin. In conclusion, BMSCs promoted mitophagy and inhibited apoptosis and pyroptosis of RTECs in kidney tissues by upregulating SIRT1/Parkin, thereby ameliorating SI-AKI.

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Section: Discussionmentioning

confidence: 99%

Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Sepsis-Induced Acute Kidney Injury by Promoting Mitophagy of Renal Tubular Epithelial Cells via the SIRT1/Parkin Axis

2021

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“…The genomic integrity of cells is extremely important for cell growth as well as successful transmission of genetic information to the next generation 54 , However, many types of external or internal genotoxic insults challenge DNA integrity 55 , forcing the host to evolve and develop compensatory changes to combat DNA damage and maintain genomic integrity 56 via several independent or complementary DNA repair pathways, allowing for a fail-safe mechanism whereby the disruption of one pathway will be compensated for by another pathway 57 . During cancer cell evolution, multiple comprehensive molecular signaling pathways have been developed to face the challenge of radiation stress, and this ability to evolve can contribute to increased cancer cell RR, leading to radiotherapy failure.…”

Section: Dsbs Are a Major Pattern Of Riddmentioning

confidence: 99%

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Huang

Zhou

2020

Sig Transduct Target Ther

673

457

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Radiotherapy is one of the most common countermeasures for treating a wide range of tumors. However, the radioresistance of cancer cells is still a major limitation for radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers for improving the outcomes of radiotherapy. DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs), including those helping cells recover from radiation injuries, such as the activation of DNA damage sensing and early transduction pathways, cell cycle arrest, and DNA repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy for overcoming tumor radioresistance, and some important advances and breakthroughs have already been achieved in recent years. On the basis of comprehensively reviewing the DDR signal pathways, we provide an update on the novel and promising druggable targets emerging from DDR pathways that can be exploited for radiosensitization. We further discuss recent advances identified from preclinical studies, current clinical trials, and clinical application of chemical inhibitors targeting key DDR proteins, including DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia-telangiectasia mutated and Rad3-related), the MRN (MRE11-RAD50-NBS1) complex, the PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, and HIF-1 (hypoxia-inducible factor-1). Challenges for ionizing radiation-induced signal transduction and targeted therapy are also discussed based on recent achievements in the biological field of radiotherapy.

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“…Recently, a direct evidence has been showed that the induction of autophagy-regulated DNA damage response via ataxia telangiectasia mutated (ATM)-mediated activation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and poly(ADP-ribose) polymerase (PARP)-1 in response to capsaicin [115]. An enhanced DNA damage response is also induced by autophagy via homologous recombination (HR) repair pathway, which is a major way of repairing double-strand breaks [116]. Moreover, the stimulated autophagy induced by epirubicin (EPI) can increase drug efflux by P-glycoprotein (P-gp), encoded MDR genes which reduce intracellular concentrations of drugs, and downregulate the NF-κB signaling pathway, which decreases the rate of apoptosis, and thereby cause EPI resistance [117].…”

Section: Autophagy As a Guardian In Tumor Drug Resistancementioning

confidence: 99%

Targeting autophagy to overcome drug resistance: further developments

2020

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Inhibiting cell survival and inducing cell death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins and damaged or aged cellular organelles to recycle their constituent metabolites that enable the maintenance of cell survival and genetic stability and even promotes the drug resistance, which severely limits the efficacy of chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect to suppress and promote tumor survival, which makes the effect of targeting autophagy on drug resistance more confusing and fuzzier. In the review, we summarize the regulation of autophagy by emerging ways, the action of targeting autophagy on drug resistance and some of the new therapeutic approaches to treat tumor drug resistance by interfering with autophagy-related pathways. The full-scale understanding of the tumor-associated signaling pathways and physiological functions of autophagy will hopefully open new possibilities for the treatment of tumor drug resistance and the improvement in clinical outcomes.

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Entrenching role of cell cycle checkpoints and autophagy for maintenance of genomic integrity

Cited by 70 publications

References 160 publications

Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Sepsis-Induced Acute Kidney Injury by Promoting Mitophagy of Renal Tubular Epithelial Cells via the SIRT1/Parkin Axis

Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Sepsis-Induced Acute Kidney Injury by Promoting Mitophagy of Renal Tubular Epithelial Cells via the SIRT1/Parkin Axis

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Targeting autophagy to overcome drug resistance: further developments

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