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Dna repair and autophagy

Vibhuti Joshi, Ayeman Amanullah, Arun Upadhyay, Ribhav Mishra, Amit Kumar, Amit Mishra
Cells regularly synthesize new proteins to replace old and abnormal proteins for normal cellular functions. Two significant protein quality control pathways inside the cellular milieu are ubiquitin proteasome system (UPS) and autophagy. Autophagy is known for bulk clearance of cytoplasmic aggregated proteins, whereas the specificity of protein degradation by UPS comes from E3 ubiquitin ligases. Few E3 ubiquitin ligases, like C-terminus of Hsc70-interacting protein (CHIP) not only take part in protein quality control pathways, but also plays a key regulatory role in other cellular processes like signaling, development, DNA damage repair, immunity and aging...
2016: Frontiers in Molecular Neuroscience
Lelin Hu, Hao Wang, Li Huang, Yong Zhao, Junjie Wang
Autophagy induced by radiation is critical to cell fate decision. Evidence now sheds light on the importance of autophagy induced by cancer radiotherapy. Traditional view considers radiation can directly or indirectly damage DNA which can activate DNA damage the repair signaling pathway, a large number of proteins participating in DNA damage repair signaling pathway such as p53, ATM, PARP1, FOXO3a, mTOR and SIRT1 involved in autophagy regulation. However, emerging recent evidence suggests radiation can also cause injury to extranuclear targets such as plasma membrane, mitochondria and endoplasmic reticulum (ER) and induce accumulation of ceramide, ROS, and Ca2+ concentration which activate many signaling pathways to modulate autophagy...
October 5, 2016: International Journal of Oncology
Prabhakar Bastola, Lisa Neums, Frank J Schoenen, Jeremy Chien
Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis...
September 28, 2016: Molecular Oncology
Jingli Hao, Peter Graham, Lei Chang, Jie Ni, Valerie Wasinger, Julia Beretov, Junli Deng, Wei Duan, Joseph Bucci, David Malouf, David Gillatt, Yong Li
Radioresistance is a major challenge for prostate cancer (CaP) metastasis and recurrence after radiotherapy. This study aimed to identify potential protein markers and signaling pathways associated with radioresistance using a PC-3 radioresistant (RR) subcutaneous xenograft mouse model and verify the radiosensitization effect from a selected potential candidate. PC-3RR and PC-3 xenograft tumors were established and differential protein expression profiles from two groups of xenografts were analyzed using liquid chromatography tandem-mass spectrometry...
September 30, 2016: Oncotarget
Zeng-Fu Shang, Qiang Wei, Lan Yu, Fang Huang, Bei-Bei Xiao, Hongtao Wang, Man Song, Li Wang, Jianguang Zhou, Jian Wang, Shanhu Li
Radiotherapy is promising and effective for treating prostate cancer but the addition of a tumor cell radiosensitizer would improve therapeutic outcomes. PC-1/PrLZ, a TPD52 protein family member is frequently upregulated in advanced prostate cancer cells and may be a biomarker of aggressive prostate cancer. Therefore, we investigated the potential role of PC-1/PrLZ for increasing radioresistance in human prostate cancer cell lines. Growth curves and survival assays after g-ray irradiation confirmed that depletion of endogenous PC-1/PrLZ significantly increased prostate cancer cell radiosensitivity...
September 20, 2016: Oncotarget
José Carlos Páez-Franco, Ignacio González-Sánchez, Nora A Gutiérrez-Nájera, Lilián G Valencia-Turcotte, Alfonso Lira-Rocha, Marco A Cerbón, Rogelio Rodríguez-Sotres
9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinolone (D3ClP) is a bioisostere of N-(4-(acridin-9-ylamino)-3-methoxyphenyl)methanesulfonamide (m-AMSA) a DNA topoisomerase II inhibitor with proven cytotoxic activity and known to induce DNA damage and apoptotic cell death in K562 cells. However, recent evidence is not consistent with DNA topoisomerase II (DNA TOP2) as the primary target of D3ClP, in contrast to m-AMSA. We provide evidence of histone γH2AX phosphorylation at Ser135 in HeLa cells treated with D3ClP, a marker of DNA double strand repair through Mre11-Rad50-Nbs1 (MRN) pathway...
September 29, 2016: Journal of Cellular Biochemistry
Kyeoung-Hwa Kim, Ji-Hoon Park, Eun-Young Kim, Jung-Jae Ko, Kyung-Soon Park, Kyung-Ah Lee
Rad51 is a conserved eukaryotic protein that mediates the homologous recombination repair of DNA double-strand breaks that occur during mitosis and meiosis. In addition, Rad51 promotes mitochondrial DNA synthesis when replication stress is increased. Rad51 also regulates cell cycle progression by preserving the G2/M transition in embryonic stem cells. In this study, we report a novel function of Rad51 in regulating mitochondrial activity during in vitro maturation of mouse oocytes. Suppression of Rad51 by injection of Rad51 dsRNA into germinal vesicle-stage oocytes resulted in arrest of meiosis in metaphase I...
September 28, 2016: Scientific Reports
Hongxing Ye, Mantao Chen, Fei Cao, Hongguang Huang, Renya Zhan, Xiujue Zheng
BACKGROUND: Glioblastoma is refractory to conventional treatment, which is combined of surgery, chemotherapy and radiotherapy. Recent studies have shown that glioma initiating cells (GICs) contribute to tumorigenesis and radioresistance. Recently, other studies showed that the GICs use the autophagy as the major pathway to survive. Chloroquine, an anti-malarial chemical, is an autophagic inhibitor which blocks autophagosome fusion with lysosome and slows down lysosomal acidification. The aim of this study was to explore the mechanisms of chloroquine on the radiosensitivity of GICs...
2016: BMC Neurology
Koji Takayama, Yohei Kawakami, Mitra Lavasani, Xiaodong Mu, James H Cummins, Takashi Yurube, Ryosuke Kuroda, Masahiro Kurosaka, Freddie H Fu, Paul D Robbins, Laura J Niedernhofer, Johnny Huard
Mice expressing reduced levels of ERCC1-XPF (Ercc1(-/Δ) mice) demonstrate premature age-related changes due to their reduced capability to repair DNA damage. Muscle-derived stem/progenitor cells (MDSPCs) isolated from Ercc1(-/Δ) mice demonstrated an impaired capacity for cell differentiation. The mammalian target of rapamycin (mTOR) is a critical regulator of cell growth in response to the availability of nutrients, hormones and oxygen levels. Inhibition of the mTOR pathway has been shown to extend the lifespans of several different species...
August 30, 2016: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Kothanahalli S Raghu, Bhanuvalli R Shamprasad, Kabekkodu S Prasada, Puspendu Paladhi, Manjunath B Joshi, Marthandavarma S Valiathan, Kanive P Guruprasad, Kapaettu Satyamoorthy
ETHNOPHARMACOLOGICAL RELEVANCE: Indian traditional medicinal system in Ayurveda suggests several preparations, known as medhya rasayanas, of diverse plant origin to enhance the health in general, reduce stress and improve brain function in particular during ageing. These effects in the context of contemporary knowledge and the underlying mechanisms are not clearly understood. Autophagy and DNA damage induced repair are inter-related quintessential pathways and are significantly altered during stress and ageing...
July 25, 2016: Journal of Ethnopharmacology
Yongfei Yang, Christine Quach, Chengyu Liang
Ultraviolet (UV)-induced DNA damage is a major risk factor for skin cancers including melanoma. UVRAG, originally identified to complement UV sensitivity in xeroderma pigmentosum (XP), has since been implicated in modulating macroautophagy/autophagy, in coordinating different intracellular trafficking pathways, and in maintaining chromosomal stability. Intriguingly, our recent study has demonstrated that UVRAG plays an essential role in protecting cells from UV-induced DNA damage by activating the nucleotide excision repair (NER) pathway...
September 2016: Autophagy
Weiwei Lin, Na Yuan, Zhen Wang, Yan Cao, Yixuan Fang, Xin Li, Fei Xu, Lin Song, Jian Wang, Han Zhang, Lili Yan, Li Xu, Xiaoying Zhang, Suping Zhang, Jianrong Wang
No abstract text is available yet for this article.
2016: Scientific Reports
Graeme Hewitt, Bernadette Carroll, Rezazadeh Sarallah, Clara Correia-Melo, Mikołaj Ogrodnik, Glyn Nelson, Elsje G Otten, Diego Manni, Robin Antrobus, Brian A Morgan, Thomas von Zglinicki, Diana Jurk, Andrei Seluanov, Vera Gorbunova, Terje Johansen, João F Passos, Viktor I Korolchuk
SQSTM1/p62 (sequestosome 1) selectively targets polyubiquitinated proteins for degradation via macroautophagy and the proteasome. Additionally, SQSTM1 shuttles between the cytoplasmic and nuclear compartments, although its role in the nucleus is relatively unknown. Here, we report that SQSTM1 dynamically associates with DNA damage foci (DDF) and regulates DNA repair. Upon induction of DNA damage SQSTM1 interacts with FLNA (filamin A), which has previously been shown to recruit DNA repair protein RAD51 (RAD51 recombinase) to double-strand breaks and facilitate homologous recombination (HR)...
July 8, 2016: Autophagy
Yong Li, Fen Liu, Yong Wang, Donghai Li, Fei Guo, Liyao Xu, Zhengguo Zeng, Xiaojun Zhong, Kejian Qian
BACKGROUND: Autophagy has been reported to increase in cancer cells after radiation. However, it remains unknown whether increased autophagy as a result of radiation affects DNA damage repair and sensitizes cancer cells. In this study, the radiosensitization effect of rapamycin, a mammalian target of rapamycin inhibitor that induces autophagy, on human lung adenocarcinoma A549 cells was investigated. METHODS: A549 cells were treated with different concentrations of rapamycin...
July 2016: Thoracic Cancer
Yanan Wang, Nan Zhang, Luyao Zhang, Ran Li, Wan Fu, Ke Ma, Xue Li, Lina Wang, Jiadong Wang, Hongquan Zhang, Wei Gu, Wei-Guo Zhu, Ying Zhao
Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome, and loss of autophagy has been linked to increased genome instability. Here, we report that loss of autophagy is coupled to reduced histone H2A ubiquitination after DNA damage. p62/SQSTM1, which accumulates in autophagy-defective cells, directly binds to and inhibits nuclear RNF168, an E3 ligase essential for histone H2A ubiquitination and DNA damage responses. As a result, DNA repair proteins such as BRCA1, RAP80, and Rad51 cannot be recruited to the sites of DNA double-strand breaks (DSBs), which impairs DSB repair...
July 7, 2016: Molecular Cell
Chao He, Lun Li, Xuan Guan, Li Xiong, Xiongying Miao
PURPOSE: To review mechanisms underlying mutant p53 (mutp53) gain of function (GOF) and mutp53-induced chemoresistance, and to investigate the role of mutp53 in response to clinical chemotherapy. METHODS: We searched the PubMed database for clinical studies from the past decade, including data evaluating the impact of mutp53 in clinical chemotherapy response. RESULTS: Interactions between mutp53 and transcriptional factors, proteins or DNA structures, as well as epigenetic regulation, contribute to mutp53 GOF...
June 21, 2016: Chemotherapy
Paulina Tokarz, Agnieszka Wanda Piastowska-Ciesielska, Kai Kaarniranta, Janusz Blasiak
Age-related macular degeneration (AMD) is characterized by the progressive degradation of photoreceptors and retinal pigment epithelium (RPE) cells. ARPE-19 is an RPE cell line established as an in vitro model for the study of AMD pathogenesis. Oxidative stress is an AMD pathogenesis factor that induces DNA damage. Thus, the oxidative stress-mediated DNA damage response (DDR) of ARPE-19 cells can be important in AMD pathogenesis. The metabolism of retinoids-which regulates cell proliferation, differentiation, and the visual cycle in the retina-was reported to be disturbed in AMD patients...
2016: International Journal of Molecular Sciences
Kai Zheng, Yan Li, Shaoxiang Wang, Xiao Wang, Chenghui Liao, Xiaopeng Hu, Long Fan, Qiangrong Kang, Yong Zeng, Xuli Wu, Haiqiang Wu, Jian Zhang, Yifei Wang, Zhendan He
Modulation of autophagy has been increasingly regarded as a promising cancer therapeutic approach. In this study, we screened several ginsenosides extracted from Panax ginseng and identified ginsenoside Ro (Ro) as a novel autophagy inhibitor. Ro blocked the autophagosome-lysosome fusion process by raising lysosomal pH and attenuating lysosomal cathepsin activity, resulting in the accumulation of the autophagosome marker MAP1LC3B/LC3B and SQSTM1/p62 (sequestosome 1) in various esophageal cancer cell lines. More detailed studies demonstrated that Ro activated ESR2 (estrogen receptor 2), which led to the activation of NCF1/p47(PHOX) (neutrophil cytosolic factor 1), a subunit of NADPH oxidase, and subsequent reactive oxygen species (ROS) production...
September 2016: Autophagy
David A Gillespie, Kevin M Ryan
Autophagy delivers damaged cytoplasmic constituents to lysosomes for degradation, thus preserving cellular integrity and protecting against disease. Remarkably, autophagy-deficient cells also exhibit aberrant DNA damage responses with therapeutic implications, such as suppression of checkpoint kinase-1 function, impaired DNA double-strand break repair by homologous recombination, and increased reliance on error-prone non-homologous end-joining for survival.
January 2016: Molecular & Cellular Oncology
Ying Zhu, Ke-Ke Zhao, Yao Tong, Ya-Li Zhou, Yi-Xiao Wang, Pei-Quan Zhao, Zhao-Yang Wang
Increased oxidative stress, which can lead to the retinal pigment epithelium (RPE) cell death by inducing ATP depletion and DNA repair, is believed to be a prominent pathology in age-related macular degeneration (AMD). In the present study, we showed that and 0.1 mM nicotinamide adenine dinucleotide (NAD(+)) administration significantly blocked RPE cell death induced by 300 μM H2O2. Further investigation showed that H2O2 resulted in increased intracellular ROS level, activation of PARP-1 and subsequently necrotic death of RPE cells...
2016: Scientific Reports
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