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Melissa Resto, Bong-Hyun Kim, Alfonso G Fernandez, Brian J Abraham, Keji Zhao, Brian A Lewis
We describe here the identification and functional characterization of the enzyme O-GlcNAcase (OGA) as an RNA polymerase II elongation factor. Using in vitro transcription elongation assays, we show that OGA activity is required for elongation in a crude nuclear extract system, while in a purified system devoid of OGA, the addition of rOGA inhibited elongation. Furthermore, OGA is physically associated with the known RNA pol II pausing/elongation factors SPT5 and TRIM28/KAP1/TIF1b, and a purified OGA/SPT5/TIF1b complex has elongation properties...
September 6, 2016: Journal of Biological Chemistry
Y Jiang, H-C Chen, X Su, P A Thompson, X Liu, K-A Do, W Wierda, M J Keating, W Plunkett
Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients exhibit del(11q22-23) before treatment, this cohort increases to over 40% upon progression following chemoimmunotherapy. The coding sequence of the DNA damage response gene, ataxia-telangiectasia-mutated (ATM), is contained in this deletion. The residual ATM allele is frequently mutated, suggesting a relationship between gene function and clinical response. To investigate this possibility, we sought to develop and validate an assay for the function of ATM protein in these patients...
2016: Blood Cancer Journal
Chun-Ting Cheng, Ching-Ying Kuo, Ching Ouyang, Chien-Feng Li, Yiyin Chung, David C Chan, Hsing-Jien Kung, David K Ann
Mitochondrial dynamics during nutrient starvation of cancer cells likely exert profound effects on their capability for metastatic progression. Here, we report that KAP1 (TRIM28), a transcriptional coadaptor protein implicated in metastatic progression in breast cancer, is a pivotal regulator of mitochondrial fusion in glucose-starved cancer cells. Diverse metabolic stresses induced Ser473 phosphorylation of KAP1 (pS473-KAP1) in a ROS- and p38-dependent manner. Results from live-cell imaging and molecular studies revealed that during the first 6 to 8 hours of glucose starvation, mitochondria initially underwent extensive fusion, but then subsequently fragmented in a pS473-KAP1-dependent manner...
September 1, 2016: Cancer Research
Masayoshi Ikeuchi, Yasunori Fukumoto, Takuya Honda, Takahisa Kuga, Youhei Saito, Naoto Yamaguchi, Yuji Nakayama
An increase in Src activity is commonly observed in epithelial cancers. Aberrant activation of the kinase activity is associated with malignant progression. However, the mechanisms that underlie the Src-induced malignant progression of cancer are not completely understood. We show here that v-Src, an oncogene that was first identified from a Rous sarcoma virus and a mutant variant of c-Src, leads to an increase in the number of anaphase and telophase cells having chromosome bridges. v-Src increases the number of γH2AX foci, and this increase is inhibited by treatment with PP2, a Src kinase inhibitor...
2016: International Journal of Molecular Sciences
Yvonne Lorat, Stefanie Schanz, Claudia E Ruebe
PURPOSE: Intensity-modulated radiotherapy (IMRT) enables the delivery of high doses to target volume while sparing surrounding non-targeted tissues. IMRT treatment, however, substantially increases the normal-tissue volume receiving low-dose irradiation, but the biological consequences are unclear. EXPERIMENTAL DESIGN: Using mouse strains that varied in genetic DNA repair capacity, we investigated the DNA damage response of cortical neurons during daily low-dose irradiation (0...
May 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bryndon J Oleson, Katarzyna A Broniowska, Aaron Naatz, Neil Hogg, Vera L Tarakanova, John A Corbett
Nitric oxide, produced in pancreatic β cells in response to proinflammatory cytokines, plays a dual role in the regulation of β-cell fate. While nitric oxide induces cellular damage and impairs β-cell function, it also promotes β-cell survival through activation of protective pathways that promote β-cell recovery. In this study, we identify a novel mechanism in which nitric oxide prevents β-cell apoptosis by attenuating the DNA damage response (DDR). Nitric oxide suppresses activation of the DDR (as measured by γH2AX formation and the phosphorylation of KAP1 and p53) in response to multiple genotoxic agents, including camptothecin, H2O2, and nitric oxide itself, despite the presence of DNA damage...
August 1, 2016: Molecular and Cellular Biology
Iván D'Orso
RNA polymerase II (Pol II) pausing at promoter-proximal regions is a highly regulated step in the transcription cycle. Pause release is facilitated by the P-TEFb kinase, which phosphorylates Pol II and negative elongation factors. Recent studies suggest that P-TEFb (as part of the inhibitory 7SK snRNP) is recruited to promoter-proximal regions through interaction with KAP1/TRIM28/TIF1β to facilitate 'on-site' kinase activation and transcription elongation. Here, I discuss features of this model and future challenges to further hone our understanding of transcriptional regulation including Pol II pausing and pause release...
June 2, 2016: RNA Biology
Yanying Wang, Jianxin Jiang, Qun Li, Hong Ma, Zengguang Xu, Yong Gao
BACKGROUND: The transcriptional regulator in embryonic development, KAP1, has been proved could promote cell proliferation and metastatic progression in a variety of human cancers. However, the role of KAP1 in hepatocellular carcinoma (HCC) remains unclear. The purpose of this study is to investigate the relationship of KAP1 expression with the progression and prognosis of HCC. METHODS: We measured the expression level of KAP1 in both human hepatoma cell lines and HCC tissues obtained from HCC patients by real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot...
April 19, 2016: International Journal of Clinical Oncology
Haibo Zhang, Ji Luo
This review discusses our current understanding of the small ubiquitin-like modifier (SUMO) pathway and how it functionally intersects with Ras signaling in cancer. The Ras family of small GTPases are frequently mutated in cancer. The role of the SUMO pathway in cancer and in Ras signaling is currently not well understood. Recent studies have shown that the SUMO pathway can both regulate Ras/MAPK pathway activity directly and support Ras-driven oncogenesis through the regulation of proteins that are not direct Ras effectors...
April 2, 2016: Small GTPases
Gabriela Ecco, Marco Cassano, Annamaria Kauzlaric, Julien Duc, Andrea Coluccio, Sandra Offner, Michaël Imbeault, Helen M Rowe, Priscilla Turelli, Didier Trono
KRAB-containing zinc finger proteins (KRAB-ZFPs) are early embryonic controllers of transposable elements (TEs), which they repress with their cofactor KAP1 through histone and DNA methylation, a process thought to result in irreversible silencing. Using a target-centered functional screen, we matched murine TEs with their cognate KRAB-ZFP. We found the paralogs ZFP932 and Gm15446 to bind overlapping but distinguishable subsets of ERVK (endogenous retrovirus K), repress these elements in embryonic stem cells, and regulate secondarily the expression of neighboring genes...
March 21, 2016: Developmental Cell
Ryan P McNamara, Carlos Guzman, Jonathan E Reeder, Iván D'Orso
The transition of RNA polymerase II (Pol II) from transcription initiation into productive elongation in eukaryotic cells is regulated by the P-TEFb kinase, which phosphorylates the C-terminal domain of paused Pol II at promoter-proximal regions. Our recent study found that P-TEFb (in an inhibited state bound to the 7SK snRNP complex) interacts with the KAP1/TRIM28 transcriptional regulator, and that KAP1 and the 7SK snRNP co-occupy most gene promoters containing paused Pol II. Here we provide a detailed experimental description and analysis of the ChIP-seq datasets that have been deposited into Gene Expression Omnibus (GEO): GS72622, so that independent groups can replicate and expand upon these findings...
March 2016: Genomics Data
Gabriela Ecco, Helen M Rowe, Didier Trono
Deposition of epigenetic marks is an important layer of the transcriptional control of retrotransposons, especially during early embryogenesis. Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are one of the largest families of transcription factors, and collectively partake in this process by tethering to thousands of retroelement-containing genomic loci their cofactor KAP1, which acts as a scaffold for a heterochromatin-inducing machinery. However, while the sequence-specific DNA binding potential of the poly-zinc finger-containing KRAB-ZFPs is recognized, very few members of the family have been assigned specific targets...
2016: Methods in Molecular Biology
Lorenzo Alibardi
Hardening of the human hair shaft during cornification results from the bonding of keratins and keratin-associated proteins. In situ hybridization and light immunocytochemical studies have shown the general distribution of different keratins and some associated proteins but not determined their ultrastructural localization. I report here the localization of hair keratins, two high-sulfur keratin-associated proteins and sulfhydryl oxidase has been studied under the transmission electron microscope in the cornification zone of the human hair...
February 15, 2016: Anatomical Science International
Ching-Ying Kuo, Xu Li, Jeremy M Stark, Hsiu-Ming Shih, David K Ann
Both RNF4 and KAP1 play critical roles in the response to DNA double-strand breaks (DSBs), but the functional interplay of RNF4 and KAP1 in regulating DNA damage response remains unclear. We have previously demonstrated the recruitment and degradation of KAP1 by RNF4 require the phosphorylation of Ser824 (pS824) and SUMOylation of KAP1. In this report, we show the retention of DSB-induced pS824-KAP1 foci and RNF4 abundance are inversely correlated as cell cycle progresses. Following irradiation, pS824-KAP1 foci predominantly appear in the cyclin A (-) cells, whereas RNF4 level is suppressed in the G0-/G1-phases and then accumulates during S-/G2-phases...
2016: Cell Cycle
Didier Trono
Transposable elements (TEs) may account for up to two-thirds of the human genome, and as genomic threats they are subjected to epigenetic control mechanisms engaged from the earliest stages of embryonic development. We previously determined that an important component of this process is the sequence-specific recognition of TEs by KRAB (Krüppel-associated box)-containing zinc-finger proteins (KRAB-ZFPs), a large family of tetrapod-restricted transcription factors that act by recruiting inducers of heterochromatin formation and DNA methylation...
2015: Cold Spring Harbor Symposia on Quantitative Biology
Ryan P McNamara, Jonathan E Reeder, Elizabeth A McMillan, Curtis W Bacon, Jennifer L McCann, Iván D'Orso
The transition from transcription initiation to elongation at promoters of primary response genes (PRGs) in metazoan cells is controlled by inducible transcription factors, which utilize P-TEFb to phosphorylate RNA polymerase II (Pol II) in response to stimuli. Prior to stimulation, a fraction of P-TEFb is recruited to promoter-proximal regions in a catalytically inactive state bound to the 7SK small nuclear ribonucleoprotein (snRNP) complex. However, it remains unclear how and why the 7SK snRNP is assembled at these sites...
January 7, 2016: Molecular Cell
Yuxuan Xiao, Daniel Pollack, Miriam Andrusier, Avi Levy, Myrasol Callaway, Edward Nieves, Prabhakara Reddi, Margarita Vigodner
Recent findings suggest diverse and potentially multiple roles of small ubiquitin-like modifier (SUMO) in testicular function and spermatogenesis. However, SUMO targets remain uncharacterized in the testis due to the complex multicellular nature of testicular tissue, the inability to maintain and manipulate spermatogenesis in vitro, and the technical challenges involved in identifying low-abundance endogenous SUMO targets. In this study, we performed cell-specific identification of sumoylated proteins using concentrated cell lysates prepared with de-sumoylation inhibitors from freshly purified spermatocytes and spermatids...
February 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Shiv K Gupta, Sani H Kizilbash, Brett L Carlson, Ann C Mladek, Felix Boakye-Agyeman, Katrina K Bakken, Jenny L Pokorny, Mark A Schroeder, Paul A Decker, Ling Cen, Jeanette E Eckel-Passow, Gobinda Sarkar, Karla V Ballman, Joel M Reid, Robert B Jenkins, Roeland G Verhaak, Erik P Sulman, Gaspar J Kitange, Jann N Sarkaria
BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided...
May 2016: Journal of the National Cancer Institute
Carolin Bürck, Andreas Mund, Julia Berscheminski, Lisa Kieweg, Sarah Müncheberg, Thomas Dobner, Sabrina Schreiner
UNLABELLED: Once transported to the replication sites, human adenoviruses (HAdVs) need to ensure decondensation and transcriptional activation of their viral genomes to synthesize viral proteins and initiate steps to reprogram the host cell for viral replication. These early stages during adenoviral infection are poorly characterized but represent a decisive moment in the establishment of a productive infection. Here, we identify a novel host viral restriction factor, KAP1. This heterochromatin-associated transcription factor regulates the dynamic organization of the host chromatin structure via its ability to influence epigenetic marks and chromatin compaction...
January 2016: Journal of Virology
Nathaly Castro-Diaz, Marc Friedli, Didier Trono
Endogenous retroelements (EREs) are essential motors of evolution yet require careful control to prevent genomic catastrophes, notably during the vulnerable phases of epigenetic reprogramming that occur immediately after fertilization and in germ cells. Accordingly, a variety of mechanisms restrict these mobile genetic units. Previous studies have revealed the importance of KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor, KAP1, in the early embryonic silencing of endogenous retroviruses and so-called SVAs, but the implication of this transcriptional repression system in the control of LINE-1, the only known active autonomous retrotransposon in the human genome, was thought to be marginal...
January 2015: Mobile Genetic Elements
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