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Keh-Yang Wang, Chun-Chang Chen, Shih-Feng Tsai, Che-Kun James Shen
DNA methylation at C of CpG dyads ((m)CpG) in vertebrate genomes is essential for gene regulation, genome stability and development. We show in this study that proper functioning of post-replicative DNA mismatch repair (MMR) in mammalian cells relies on the presence of genomic (m)CpG, as well as on the maintenance DNA methyltransferase Dnmt1 independently of its catalytic activity. More importantly, high efficiency of mammalian MMR surveillance is achieved through a hemi-(m)CpG-Np95(Uhrf1)-Dnmt1 axis, in which the MMR surveillance complex(es) is recruited to post-replicative DNA by Dnmt1, requiring its interactions with MutSα, as well as with Np95 bound at the hemi-methylated CpG sites...
November 25, 2016: Scientific Reports
Hang Gyeong Chin, V K Chaithanya Ponnaluri, Guoqiang Zhang, Pierre-Olivier Estève, Scott E Schaus, Ulla Hansen, Sriharsa Pradhan
The transcription factor LSF is highly expressed in hepatocellular carcinoma (HCC) and promotes oncogenesis. Factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity and exerts anti-proliferative activity. Here, we show that LSF binds directly to the maintenance DNA (cytosine-5) methyltransferase 1 (DNMT1) and its accessory protein UHRF1 both in vivo and in vitro. Binding of LSF to DNMT1 stimulated DNMT1 activity and FQI1 negated the methyltransferase activation. Addition of FQI1 to the cell culture disrupted LSF bound DNMT1 and UHRF1 complexes, resulting in global aberrant CpG methylation...
November 10, 2016: Oncotarget
Renata Z Jurkowska, Albert Jeltsch
DNA methylation is currently one of the hottest topics in basic and biomedical research. Despite tremendous progress in understanding the structures and biochemical properties of the mammalian DNA nucleotide methyltransferases (DNMTs), principles of their regulation in cells have only begun to be uncovered. In mammals, DNA methylation is introduced by the DNMT1, DNMT3A, and DNMT3B enzymes, which are all large multi-domain proteins. These enzymes contain a catalytic C-terminal domain with a characteristic cytosine-C5 methyltransferase fold and an N-terminal part with different domains that interacts with other proteins and chromatin and is involved in targeting and regulation of the DNMTs...
2016: Advances in Experimental Medicine and Biology
Vidya Ramesh, Efil Bayam, Filippo M Cernilogar, Ian M Bonapace, Markus Schulze, Markus J Riemenschneider, Gunnar Schotta, Magdalena Götz
In order to understand whether early epigenetic mechanisms instruct the long-term behavior of neural stem cells (NSCs) and their progeny, we examined Uhrf1 (ubiquitin-like PHD ring finger-1; also known as Np95), as it is highly expressed in NSCs of the developing brain and rapidly down-regulated upon differentiation. Conditional deletion of Uhrf1 in the developing cerebral cortex resulted in rather normal proliferation and neurogenesis but severe postnatal neurodegeneration. During development, deletion of Uhrf1 lead to global DNA hypomethylation with a strong activation of the intracisternal A particle (IAP) family of endogenous retroviral elements, accompanied by an increase in 5-hydroxymethylcytosine...
October 1, 2016: Genes & Development
Dongjun Qin, Weiwei Wang, Hu Lei, Hao Luo, Haiyan Cai, Caixia Tang, Yunzhao Wu, Yingying Wang, Jin Jin, Weilie Xiao, Tongdan Wang, Chunmin Ma, Hanzhang Xu, Jinfu Zhang, Fenghou Gao, Yingli Wu
Deubiquitinating enzyme USP7 has been involved in the pathogenesis and progression of several cancers. Targeting USP7 is becoming an attractive strategy for cancer therapy. In this study, we identified synthetic triterpenoid C-28 methyl ester of 2-cyano-3, 12-dioxoolen-1, 9-dien-28-oic acid (CDDO-Me) as a novel inhibitor of USP7 but not of other cysteine proteases such as cathepsin B and cathepsin D. CDDO-Me inhibits USP7 activity via a mechanism that is independent of the presence of α, β-unsaturated ketones...
October 21, 2016: Oncotarget
Yan Jiang, Jiahong Chen, Cong Yue, Hang Zhang, Tao Chen
Trichloroethylene (TCE), a common environmental contaminant, causes hepatocellular carcinoma in mice but not in rats. To understand the mechanisms of the species-specific hepatocarcinogenecity of TCE, we examined the methylation status of DNA in the liver of rats exposed to TCE at 0 or 1000 mg/kg b.w. for 5 days using MeDIP-chip, bisulfite sequencing, COBRA, and LC-MS/MS. The related mRNA expression levels were measured by qPCR. Although no global DNA methylation change was detected, 806 genes were hypermethylated and 186 genes were hypomethylated...
October 17, 2016: Chemical Research in Toxicology
Joseph S Harrison, Evan M Cornett, Dennis Goldfarb, Paul A DaRosa, Zimeng M Li, Feng Yan, Bradley M Dickson, Angela H Guo, Daniel V Cantu, Lilia Kaustov, Peter J Brown, Cheryl H Arrowsmith, Dorothy A Erie, Michael B Major, Rachel E Klevit, Krzysztof Krajewski, Brian Kuhlman, Brian D Strahl, Scott B Rothbart
The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains...
2016: ELife
Qian Zhao, Jiqin Zhang, Ruoyu Chen, Lina Wang, Bo Li, Hao Cheng, Xiaoya Duan, Haijun Zhu, Wei Wei, Jiwen Li, Qihan Wu, Jing-Dong J Han, Wenqiang Yu, Shaorong Gao, Guohong Li, Jiemin Wong
In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Here we have generated an Uhrf1 knockin (KI) mouse model that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. The homozygous Uhrf1 KI mice are viable and fertile, and exhibit ∼10% reduction of DNA methylation in various tissues. The reduced DNA methylation occurs globally in the genome and does not restrict only to the H3K9me2/3 enriched repetitive sequences. In vitro UHRF1 binds with higher affinity to reconstituted nucleosome with hemi-methylated CpGs than that with H3K9me2/3, although it binds cooperatively to nucleosome with both modifications...
2016: Nature Communications
Kenichi Nakamura, Yoshifumi Baba, Keisuke Kosumi, Kazuto Harada, Hironobu Shigaki, Keisuke Miyake, Yuki Kiyozumi, Mayuko Ohuchi, Junji Kurashige, Takatsugu Ishimoto, Masaaki Iwatsuki, Yasuo Sakamoto, Naoya Yoshida, Masayuki Watanabe, Mitsuyoshi Nakao, Hideo Baba
BACKGROUND: Global DNA hypomethylation contributes to oncogenesis through various mechanisms. The level of long interspersed nucleotide element-1 (LINE- 1) methylation is considered a surrogate marker of global DNA methylation, and is attracting interest as a good predictor of cancer prognosis. However, the mechanism how LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully elucidated. Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays a crucial role in DNA methylation...
August 5, 2016: Oncotarget
Guangjin Ding, Peilin Chen, Hui Zhang, Xiaojie Huang, Yi Zang, Jiwen Li, Jia Li, Jiemin Wong
As a protein critical for DNA maintenance methylation and cell proliferation, UHRF1 is frequently highly expressed in various human cancers and is considered as a drug target for cancer therapy. In a high throughput screening for small molecules that induce UHRF1 protein degradation, we have identified the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). We present evidence that UHRF1 interacts with HSP90 chaperone complex and is a novel HSP90 client protein. Pharmacological inhibition of HSP90 with 17-AAG or 17-dimethylaminoethylamino-17-demethoxygeldanamycin results in UHRF1 ubiquitination and proteasome-dependent degradation...
September 16, 2016: Journal of Biological Chemistry
Yusuke Goto, Akira Kurozumi, Nijiro Nohata, Satoko Kojima, Ryosuke Matsushita, Hirofumi Yoshino, Kazuto Yamazaki, Yasuo Ishida, Tomohiko Ichikawa, Yukio Naya, Naohiko Seki
Molecular targeted therapy is a standard treatment for patients with advanced renal cell carcinoma (RCC). Sunitinib is one of the most common molecular-targeted drugs for metastatic RCC. Molecular mechanisms of sunitinib resistance in RCC cells is still ambiguous. The microRNA (miRNA) expression signature of patients with sunitinib failure in RCC was constructed using a polymerase chain reaction (PCR)-based array. Several miRNAs that were aberrantly expressed in RCC tissues from patients treated with sunitinib were identified in this analysis...
July 28, 2016: Oncotarget
Yuanhui Jia, Pishun Li, Lan Fang, Haijun Zhu, Liangliang Xu, Hao Cheng, Junying Zhang, Fei Li, Yan Feng, Yan Li, Jialun Li, Ruiping Wang, James X Du, Jiwen Li, Taiping Chen, Hongbin Ji, Jackie Han, Wenqiang Yu, Qihan Wu, Jiemin Wong
Global DNA hypomethylation is a most common epigenetic alteration in cancer, but the mechanism remains elusive. Previous studies demonstrate that UHRF1 but not UHRF2 is required for mediating DNA maintenance methylation by DNMT1. Here we report unexpectedly a conserved function for UHRF1 and UHRF2: inhibiting de novo DNA methylation by functioning as E3 ligases promoting DNMT3A degradation. UHRF1/2 are frequently overexpressed in cancers and we present evidence that UHRF1/2 overexpression downregulates DNMT3A proteins and consequently leads to DNA hypomethylation...
2016: Cell Discovery
Zhen-Yu Zhang, Jia-Jun Cai, Jin Hong, Kay Ka-Wai Li, Zhou Ping, Yin Wang, Ho-Keung Ng, Yu Yao, Ying Mao
Studies have showed the involvement of ubiquitin-like with PHD and RING finger domains 1 (UHRF1) in tumorigenesis and progression. This study focused on the relationships between UHRF1 and medulloblastoma (MB). Immunostaining and western blotting demonstrated differential expression of UHRF1 in MB tissues and no UHRF1 expression in normal cerebellum tissues. Univariate survival analysis revealed MB patients with high UHRF1 expression had significantly shorter OS and PFS than patients with low UHRF1 (OS p = 0...
September 2016: Medical Oncology
Bi-Cheng Wang, Guo-He Lin, Bo Wang, Min Yan, Bin He, Wei Zhang, An-Kui Yang, Zi-Jie Long, Quentin Liu
Anaplastic thyroid cancer (ATC), an undifferentiated subtype of thyroid cancer, is one of the most malignant endocrine cancer with low survival rate, and resistant to chemotherapy and radiation therapy. Here we found that UHRF1 was highly expressed in human ATC compared with normal tissue and papillary thyroid cancer (PTC). Knockdown of UHRF1 inhibited proliferation of ATC in vitro and in vivo. Consistently, overexpression of UHRF1 promoted the proliferation of thyroid cancer cells. Moreover, UHRF1 suppression induced differentiation of three-dimensional (3D) cultured ATC cells and down-regulated the expression of dedifferentiation marker (CD97)...
July 18, 2016: Oncotarget
Poyin Huang, Chiou-Ling Cheng, Ya-Hsuan Chang, Chia-Hsin Liu, Yi-Chiung Hsu, Jin-Shing Chen, Gee-Chen Chang, Bing-Ching Ho, Kang-Yi Su, Hsuan-Yu Chen, Sung-Liang Yu
The current staging system for non-small cell lung cancer (NSCLC) is inadequate for predicting outcome. Risk score, a linear combination of the values for the expression of each gene multiplied by a weighting value which was estimated from univariate Cox proportional hazard regression, can be useful. The aim of this study is to analyze survival-related genes with TaqMan Low-Density Array (TLDA) and risk score to explore gene-signature in lung cancer. A total of 96 NSCLC specimens were collected and randomly assigned to a training (n = 48) or a testing cohort (n = 48)...
July 16, 2016: Oncotarget
Ting-Ting Ge, Meng Yang, Zhuo Chen, Ge Lou, Tao Gu
BACKGROUND: Up-regulation of UHRF1 has been observed in a variety of cancers and appears to serve as an independent prognostic factor. OBJECTIVE: To explore the effect of UHRF1 gene silencing on apoptosis and proliferation of cervical squamous cell carcinoma (CSCC) CaSki cells. METHODS: This study consisted of 47 CSCC tissues and 40 normal cervical tissues. The CaSki cells were assigned into Blank group (CaSki cells not transfected), NC group (CaSki cells transfected with control siRNA), and UHRF1 Silence group (CaSki cells transfected with UHRF1 siRNA)...
2016: Journal of Ovarian Research
Satoru Hashimoto, Hirofumi Anai, Katsuhiro Hanada
Interstrand DNA crosslinks (ICLs) are the link between Watson-Crick strands of DNAs with the covalent bond and prevent separation of DNA strands. Since the ICL lesion affects both strands of the DNA, the ICL repair is not simple. So far, nucleotide excision repair (NER), structure-specific endonucleases, translesion DNA synthesis (TLS), homologous recombination (HR), and factors responsible for Fanconi anemia (FA) are identified to be involved in ICL repair. Since the presence of ICL lesions causes severe defects in transcription and DNA replication, mutations in these DNA repair pathways give rise to a various hereditary disorders...
2016: Genes and Environment: the Official Journal of the Japanese Environmental Mutagen Society
Ferdinand von Meyenn, Mario Iurlaro, Ehsan Habibi, Ning Qing Liu, Ali Salehzadeh-Yazdi, Fátima Santos, Edoardo Petrini, Inês Milagre, Miao Yu, Zhenqing Xie, Leonie I Kroeze, Tatyana B Nesterova, Joop H Jansen, Hehuang Xie, Chuan He, Wolf Reik, Hendrik G Stunnenberg
Global demethylation is part of a conserved program of epigenetic reprogramming to naive pluripotency. The transition from primed hypermethylated embryonic stem cells (ESCs) to naive hypomethylated ones (serum-to-2i) is a valuable model system for epigenetic reprogramming. We present a mathematical model, which accurately predicts global DNA demethylation kinetics. Experimentally, we show that the main drivers of global demethylation are neither active mechanisms (Aicda, Tdg, and Tet1-3) nor the reduction of de novo methylation...
June 16, 2016: Molecular Cell
Zhen Gui, Quanbo Wang, Jinchang Li, Mingchen Zhu, Lili Yu, Tang Xun, Feng Yan, Huangxian Ju
As an emerging noninvasive blood biomarker, circulating free DNA (cfDNA) can be utilized to assess diagnosis, progression and evaluate prognosis of cancer. However, cfDNAs are not "naked", they can be part of complexes, or are bound to the surface of the cells via proteins, which make the detection more challenging. Here, a simple method for the detection of Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) DNA exacted from serum of breast cancer (BC) has been developed using a novel locked nucleic acid molecular beacon (LNA-MB)...
July 1, 2016: Talanta
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