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Shengyuan Zeng, Yangyang Wang, Ting Zhang, Lu Bai, Yalan Wang, Changzhu Duan
UHRF2 is a ubiquitin-protein ligase E3 that regulates cell cycle, genomic stability and epigenetics. We conducted a co-immunoprecipitation assay and found that TIP60 and HDAC1 interact with UHRF2. We previously demonstrated that UHRF2 regulated H3K9ac and H3K14ac differentially in normal and cancer cells. However, the accurate signal transduction mechanisms were not clear. In this study, we found that TIP60 acted downstream of UHRF2 to regulate H3K9ac and H3K14ac expression. TIP60 is stabilized in normal cells by UHRF2 ubiquitination...
October 14, 2016: Protein & Cell
Garren M Low, David S Thylur, Vicky N Yamamoto, Uttam K Sinha
Much of the current literature regarding the molecular pathophysiology of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has focused on the virus's effect on cell cycle modulation and cell proliferation. A second mechanism of pathogenicity employed by HPV, dysregulation of cellular DNA repair processes, has been more sparsely studied. The purpose of this review is to describe current understanding about the effect of HPV on DNA repair in HNSCC, taking cues from cervical cancer literature...
October 2016: Oral Oncology
T Brooke McClendon, Rana Mainpal, Francis Raj Gandhi Amrit, Michael W Krause, Arjumand Ghazi, Judith L Yanowitz
The germ line efficiently combats numerous genotoxic insults to ensure the high fidelity propagation of unaltered genomic information across generations. Yet, germ cells in most metazoans also intentionally create double-strand breaks (DSBs) to promote DNA exchange between parental chromosomes, a process known as crossing over. Homologous recombination is employed in the repair of both genotoxic lesions and programmed DSBs and many of the core DNA repair proteins function in both processes. In addition, DNA repair efficiency and crossover distribution are both influenced by local and global differences in chromatin structure, yet the interplay between chromatin structure, genome integrity, and meiotic fidelity is still poorly understand...
October 5, 2016: G3: Genes—Genomes—Genetics
Xiaoli Zhang, Jiyong Wu, Yepeng Luan
Tip60, the founding member of MYST histone acetyltransferase family, was originally identified as a cellular acetyltransferase protein that interacts with HIV-1 Tat. Tip60 plays roles in many processes such as cellular signaling transmission, DNA damage repair, cell cycle and checkpoint control and apoptosis by acetylating its histone or non-histone substrates. Dysfunction of Tip60 could promote or suppress diseases including different kinds of cancers. Here, some main functions and its known inhibitors were summarized...
September 23, 2016: Mini Reviews in Medicinal Chemistry
Ling-Jun Zhao, Paul M Loewenstein, Maurice Green
The adenovirus E1A 243R oncoprotein targets TRRAP, a scaffold protein that assembles histone acetyltransferase (HAT) complexes, such as the NuA4/Tip60 complex which mediates transcriptional activity of the proto-oncogene MYC and helps determine the cancer cell phenotype. How E1A transforms cells through TRRAP remains obscure. We performed proteomic analysis with the N-terminal transcriptional repression domain of E1A 243R (E1A 1-80) and showed that E1A 1-80 interacts with TRRAP, p400, and three other members of the NuA4 complex - DMAP1, RUVBL1 and RUVBL2 - not previously shown to associate with E1A 243R...
September 21, 2016: Virology
Yanzhou Zhang, Vanitha Krishna Subbaiah, Deepa Rajagopalan, Cheng Yong Tham, Lissa Nurrul Abdullah, Tan Boon Toh, Min Gong, Tuan Zea Tan, Shweta Pradip Jadhav, Amit Kumar Pandey, Neerja Karnani, Edward Kai-Hua Chow, Jean Paul Thiery, Sudhakar Jha
HIV-Tat-interacting protein of 60 kDa (TIP60) is a lysine acetyltransferase and known to be downregulated in multiple cancers. Among various signalling pathways, TIP60 is implicated in regulating epithelial-mesenchymal transition (EMT). Here, we show that TIP60 expression abrogates cell migration and metastatic potential of breast cancer cells using in vitro and in vivo models. Mechanistically, we show that this is through its ability to destabilize DNMT1 and inhibit SNAIL2 function (SNAIL2-mediated EMT/cell migration)...
September 20, 2016: Journal of Molecular Cell Biology
Katharina Kolbe, Hassan Bukhari, Christina Loosse, Gregor Leonhardt, Annika Glotzbach, Magdalena Pawlas, Katharina Hess, Carsten Theiss, Thorsten Müller
Nuclear spheres are protein aggregates consisting of FE65, TIP60, BLM, and other yet unknown proteins. Generation of these structures in the cellular nucleus is putatively modulated by the amyloid precursor protein (APP), either by its cleavage or its phosphorylation. Nuclear spheres were preferentially studied in cell culture models and their existence in the human brain had not been known. Existence of nuclear spheres in the human brain was studied using immunohistochemistry. Cell culture experiments were used to study regulative mechanisms of nuclear sphere generation...
August 26, 2016: Neurobiology of Aging
Matej Horvath, Zorana Mihajlovic, Vera Slaninova, Raquel Perez Gomez, Yuri Moshkin, Alena Krejci
The silent information regulator 1 (Sirt1) has previously been shown to have negative effects on the Notch pathway in several contexts. We bring evidence that Sirt1 has a positive effect on Notch activation in Drosophila, in the context of sensory organ precursor specification and during wing development. The phenotype of Sirt1 mutant resembles weak Notch loss of function phenotypes and genetic interactions of Sirt1 with the components of the Notch pathway also suggest a positive role of Sirt1 in Notch signalling...
September 13, 2016: Biochemical Journal
James A L Brown, Emer Bourke, Leif A Eriksson, Michael J Kerin
Two opposing enzyme classes regulate fundamental elements of genome maintenance, gene regulation and metabolism, either through addition of an acetyl moiety by histone acetyltransferases (HATs) or its removal by histone de-acetyltransferases (HDAC), and are exciting targets for drug development. Importantly, dysfunctional acetylation has been implicated in numerous diseases, including cancer. Within the HAT superfamily the MYST family holds particular interest, as its members are directly involved in the DNA damage response and repair pathways and crucially, several members have been shown to be down-regulated in common cancers (such as breast and prostate)...
August 15, 2016: Biochemical Society Transactions
Marek Adamowicz, Jelena Vermezovic, Fabrizio d'Adda di Fagagna
The DNA damage response (DDR) signal transduction pathway is responsible for sensing DNA damage and further relaying this signal into the cell. ATM is an apical DDR kinase that orchestrates the activation and the recruitment of downstream DDR factors to induce cell-cycle arrest and repair. We have previously shown that NOTCH1 inhibits ATM activation upon DNA damage, but the underlying mechanism remains unclear. Here, we show that NOTCH1 does not impair ATM recruitment to DNA double-strand breaks (DSBs). Rather, NOTCH1 prevents binding of FOXO3a and KAT5/Tip60 to ATM through a mechanism in which NOTCH1 competes with FOXO3a for ATM binding...
August 23, 2016: Cell Reports
Suzanna R Hopkins, Grant A McGregor, Johanne M Murray, Jessica A Downs, Velibor Savic
In recent years, research into synthetic lethality and how it can be exploited in cancer treatments has emerged as major focus in cancer research. However, the lack of a simple to use, sensitive and standardised assay to test for synthetic interactions has been slowing the efforts. Here we present a novel approach to synthetic lethality screening based on co-culturing two syngeneic cell lines containing individual fluorescent tags. By associating shRNAs for a target gene or control to individual fluorescence labels, we can easily follow individual cell fates upon siRNA treatment and high content imaging...
October 2016: DNA Repair
Songjun Xu, Priyalakshmi Panikker, Sahira Iqbal, Felice Elefant
Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer's disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model...
2016: PloS One
Joel I Perez-Perri, Veronica L Dengler, K Audrey Audetat, Ahwan Pandey, Elizabeth A Bonner, Marjeta Urh, Jacqui Mendez, Danette L Daniels, Pablo Wappner, Matthew D Galbraith, Joaquín M Espinosa
Hypoxia-inducible factors (HIFs) are critical regulators of the cellular response to hypoxia. Despite their established roles in normal physiology and numerous pathologies, the molecular mechanisms by which they control gene expression remain poorly understood. We report here a conserved role for the TIP60 complex as a HIF1 transcriptional cofactor in Drosophila and human cells. TIP60 (KAT5) is required for HIF1-dependent gene expression in fly cells and embryos and colorectal cancer cells. HIF1A interacts with and recruits TIP60 to chromatin...
June 28, 2016: Cell Reports
Charlene Siew-Hon Tan, Christabel Fung-Yih Ho, Swan-Ser Heng, Jui-Sheng Wu, Benny Kwong-Huat Tan, Yee-Kong Ng, Grace Y Sun, Teng-Nan Lin, Wei-Yi Ong
Clinacanthus nutans Lindau (C. nutans), commonly known as Sabah Snake Grass in southeast Asia, is widely used in folk medicine due to its analgesic, antiviral, and anti-inflammatory properties. Our recent study provided evidence for the regulation of cytosolic phospholipase A2 (cPLA2) mRNA expression by epigenetic factors (Tan et al. in Mol Neurobiol. doi: 10.1007/s12035-015-9314-z , 2015). This enzyme catalyzes the release of arachidonic acid from glycerophospholipids, and formation of pro-inflammatory eicosanoids or toxic lipid peroxidation products such as 4-hydroxynonenal...
September 2016: Neuromolecular Medicine
Soumyajit Banerjee Mustafi, Prabir Kumar Chakraborty, Sarwat Naz, Shailendra Kumar Dhar Dwivedi, Mark Street, Rumki Basak, Da Yang, Kai Ding, Priyabrata Mukherjee, Resham Bhattacharya
Chemotherapy-induced emergence of drug resistant cells is frequently observed and is exemplified by the expression of family of drug resistance proteins including, multidrug resistance protein 1 (MDR1). However, a concise mechanism for chemotherapy-induced MDR1 expression is unclear. Mechanistically, mutational selection, epigenetic alteration, activation of the Wnt pathway or impaired p53 function have been implicated. The present study describes that the surviving fraction of cisplatin resistant cells co- upregulate MDR1, BMI1 and acetyl transferase activity of TIP60...
August 2016: Biochimica et Biophysica Acta
Karine Jacquet, Amélie Fradet-Turcotte, Nikita Avvakumov, Jean-Philippe Lambert, Céline Roques, Raj K Pandita, Eric Paquet, Pauline Herst, Anne-Claude Gingras, Tej K Pandita, Gaëlle Legube, Yannick Doyon, Daniel Durocher, Jacques Côté
The NuA4/TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here we identified MBTD1 as a stable subunit of the complex, and we reveal that, via a histone reader domain for H4K20me1/2, MBTD1 allows TIP60 to associate with specific gene promoters and to promote the repair of DNA double-strand breaks by homologous recombination. It was previously suggested that TIP60-dependent acetylation of H4 regulates binding of the non-homologous end joining factor 53BP1, which engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub...
May 5, 2016: Molecular Cell
Yi-Li Feng, Ji-Feng Xiang, Na Kong, Xiu-Jun Cai, An-Yong Xie
Cellular response to DNA double-strand breaks (DSBs), the most deleterious type of DNA damage, is highly influenced by higher-order chromatin structure in eukaryotic cells. Compared with euchromatin, the compacted structure of heterochromatin not only protects heterochromatic DNA from damage, but also adds an extra layer of control over the response to DSBs occurring in heterochromatin. One key step in this response is the decondensation of heterochromatin structure. This decondensation process facilitates the DNA damage signaling and promotes proper heterochromatic DSB repair, thus helping to prevent instability of heterochromatic regions of genomes...
July 2016: Acta Biochimica et Biophysica Sinica
Sandeep Dukare, Karl-Heinz Klempnauer
The transcription factor c-Myb plays a key role in the control of proliferation and differentiation in hematopoietic progenitor cells and has been implicated in the development of leukemia and certain non-hematopoietic tumors. c-Myb activity is highly dependent on the interaction with the coactivator p300 which is mediated by the transactivation domain of c-Myb and the KIX domain of p300. We have previously observed that conservative valine-to-isoleucine amino acid substitutions in a conserved stretch of hydrophobic amino acids have a profound effect on Myb activity...
July 2016: Biochimica et Biophysica Acta
Hongmei Cui, Xingyao Li, Chunhua Han, Qi-En Wang, Hongbo Wang, Han-Fei Ding, Junran Zhang, Chunhong Yan
The response to UV irradiation is important for a cell to maintain its genetic integrity when challenged by environmental genotoxins. An immediate early response to UV irradiation is the rapid induction of activating transcription factor 3 (ATF3) expression. Although emerging evidence has linked ATF3 to stress pathways regulated by the tumor suppressor p53 and the histone acetyltransferase Tip60, the role of ATF3 in the UV response remains largely unclear. Here, we report that ATF3 mediated dichotomous UV responses...
May 13, 2016: Journal of Biological Chemistry
Min Shi, Xiao-Jie Lu, Juan Zhang, Hua Diao, Guangming Li, Ling Xu, Ting Wang, Jue Wei, Wenying Meng, Jia-Li Ma, Heguo Yu, Yu-Gang Wang
Lysine acetylation has been reported to involve in the pathogenesis of multiple diseases including cancer. In our screening study to identify natural compounds with lysine acetyltransferase inhibitor (KATi) activity, oridonin was found to possess acetyltransferase-inhibitory effects on multiple acetyltransferases including P300, GCN5, Tip60, and pCAF. In gastric cancer cells, oridonin treatment inhibited cell proliferation in a concentration-dependent manner and down-regulated the expression of p53 downstream genes, whereas p53 inhibition by PFT-α reversed the antiproliferative effects of oridonin...
April 19, 2016: Oncotarget
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