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Dna damage, kap1

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...
September 2, 2016: Blood Cancer Journal
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...
June 2, 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
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
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
Martina Magni, Vincenzo Ruscica, Michela Restelli, Enrico Fontanella, Giacomo Buscemi, Laura Zannini
Cell cycle and apoptosis regulator 2 (CCAR2, formerly known as DBC1) is a nuclear protein largely involved in DNA damage response, apoptosis, metabolism, chromatin structure and transcription regulation. Upon DNA lesions, CCAR2 is phosphorylated by the apical kinases ATM/ATR and this phosphorylation enhances CCAR2 binding to SIRT1, leading to SIRT1 inhibition, p53 acetylation and p53-dependent apoptosis. Recently, we found that also the checkpoint kinase Chk2 and the proteasome activator REGγ are required for efficient CCAR2-mediated inhibition of SIRT1 and induction of p53-dependent apoptosis...
July 10, 2015: Oncotarget
J Kim, Y Liu, M Qiu, Y Xu
The pluripotency gene Nanog is not expressed in normal adult tissues but is overexpressed in some human cancers. However, the tumorigenic roles of Nanog remain unclear. The ectopic expression of Nanog is not sufficient to induce spontaneous tumors in mice but can promote metastasis of established tumors by activating the expression of metastatic genes. The expression of Nanog in mouse skin activates tumor suppressor p53, leading to the differentiation of epidermal stem cells. In the absence of p53, Nanog induces spontaneous squamous cell carcinoma, identifying a novel role of Nanog in tumorigenesis...
March 10, 2016: Oncogene
Michal W Luczak, Samantha E Green, Anatoly Zhitkovich
BACKGROUND: Carcinogenic hexavalent chromium [Cr(VI)] requires cellular reduction to generate DNA damage. Metabolism of Cr(VI) by its principal reducer ascorbate (Asc) lacks a Cr(V) intermediate, which is abundant in reactions with a minor reducing agent, glutathione. Cultured cells are widely used in mechanistic studies of Cr(VI) toxicity; however, they typically contain < 1% of normal Asc levels. Asc deficiency is also expected to diminish protection against reactive oxygen species...
January 2016: Environmental Health Perspectives
Yi-Hui Lin, Jian Yuan, Huadong Pei, Tongzheng Liu, David K Ann, Zhenkun Lou
Homologous recombination and non-homologous end joining are two major DNA double-strand-break repair pathways. While HR-mediated repair requires a homologous sequence as the guiding template to restore the damage site precisely, NHEJ-mediated repair ligates the DNA lesion directly and increases the risk of losing nucleotides. Therefore, how a cell regulates the balance between HR and NHEJ has become an important issue for maintaining genomic integrity over time. Here we report that SIRT1-dependent KAP1 deacetylation positively regulates NHEJ...
2015: PloS One
Alkmini Kalousi, Anne-Sophie Hoffbeck, Platonas N Selemenakis, Jordan Pinder, Kienan I Savage, Kum Kum Khanna, Laurent Brino, Graham Dellaire, Vassilis G Gorgoulis, Evi Soutoglou
Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair...
April 7, 2015: Cell Reports
Mariko Morii, Yasunori Fukumoto, Sho Kubota, Noritaka Yamaguchi, Yuji Nakayama, Naoto Yamaguchi
The DNA damage checkpoint arrests cell cycle progression to allow time for DNA repair. After completion of DNA repair, checkpoint activation is terminated, and cell cycle progression is resumed in a process called checkpoint recovery. The activation of the checkpoint has been studied in depth, but little is known about recovery from the DNA damage checkpoint. Recently we showed that Src family kinases promote recovery from the G2 DNA damage checkpoint. Here we show that imatinib inhibits inactivation of ATM/ATR signaling pathway to suppress recovery from Adriamycin/doxorubicin-induced DNA damage checkpoint arrest...
August 2015: Cell Biology International
Joseph B Addison, Colton Koontz, James H Fugett, Chad J Creighton, Dongquan Chen, Mark K Farrugia, Renata R Padon, Maria A Voronkova, Sarah L McLaughlin, Ryan H Livengood, Chen-Chung Lin, J Michael Ruppert, Elena N Pugacheva, Alexey V Ivanov
KAP1 (TRIM28) is a transcriptional regulator in embryonic development that controls stem cell self-renewal, chromatin organization, and the DNA damage response, acting as an essential corepressor for KRAB family zinc finger proteins (KRAB-ZNF). To gain insight into the function of this large gene family, we developed an antibody that recognizes the conserved zinc fingers linker region (ZnFL) in multiple KRAB-ZNF. Here, we report that the expression of many KRAB-ZNF along with active SUMOlyated KAP1 is elevated widely in human breast cancers...
January 15, 2015: Cancer Research
Yulian P Ramirez, Ann C Mladek, Roger M Phillips, Mikko Gynther, Jarkko Rautio, Alonzo H Ross, Richard T Wheelhouse, Jann N Sakaria
The cellular responses to two new temozolomide (TMZ) analogues, DP68 and DP86, acting against glioblastoma multiforme (GBM) cell lines and primary culture models are reported. Dose-response analysis of cultured GBM cells revealed that DP68 is more potent than DP86 and TMZ and that DP68 was effective even in cell lines resistant to TMZ. On the basis of a serial neurosphere assay, DP68 inhibits repopulation of these cultures at low concentrations. The efficacy of these compounds was independent of MGMT and MMR functions...
January 2015: Molecular Cancer Therapeutics
Michael Van Meter, Mehr Kashyap, Sarallah Rezazadeh, Anthony J Geneva, Timothy D Morello, Andrei Seluanov, Vera Gorbunova
L1 retrotransposons are an abundant class of transposable elements that pose a threat to genome stability and may have a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of ageing; however the mechanisms underlying this phenomenon remain unknown. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity. Specifically, SIRT6 binds to the 5'-UTR of L1 loci, where it mono-ADP ribosylates the nuclear corepressor protein, KAP1, and facilitates KAP1 interaction with the heterochromatin factor, HP1α, thereby contributing to the packaging of L1 elements into transcriptionally repressive heterochromatin...
2014: Nature Communications
Chun-Ting Cheng, Ching-Ying Kuo, David K Ann
KAP1/TRIM28/TIF1β was identified nearly twenty years ago as a universal transcriptional co-repressor because it interacts with a large KRAB-containing zinc finger protein (KRAB-ZFP) transcription factor family. Many studies demonstrate that KAP1 affects gene expression by regulating the transcription of KRAB-ZFP-specific loci, trans-repressing as a transcriptional co-repressor or epigenetically modulating chromatin structure. Emerging evidence suggests that KAP1 also functions independent of gene regulation by serving as a SUMO/ubiquitin E3 ligase or signaling scaffold protein to mediate signal transduction...
August 26, 2014: World Journal of Biological Chemistry
Yasunori Fukumoto, Kazumasa Kuki, Mariko Morii, Takahito Miura, Takuya Honda, Kenichi Ishibashi, Hitomi Hasegawa, Sho Kubota, Yudai Ide, Noritaka Yamaguchi, Yuji Nakayama, Naoto Yamaguchi
DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks...
September 26, 2014: Biochemical and Biophysical Research Communications
Joana Santos, Jesús Gil
Senescence is a highly stable cell cycle arrest which limits the replication of cells with damaged genomes. The senescence program is activated during aging or in response to insults like DNA damage or oncogenic signaling. Upon induction of senescence, cells undergo profound changes on their transcription program, chromatin organization, and they secrete a complex mixture of mainly pro-inflammatory components termed the senescence-associated secretory phenotype (SASP). The SASP mediates multiple effects, including reinforcing senescence and activating immune surveillance responses...
November 2014: Immunology Letters
Lidza Kalifa, Jennifer S Gewandter, Rhonda J Staversky, Elaine A Sia, Paul S Brookes, Michael A O'Reilly
Excessive nuclear or mitochondrial DNA damage can lead to mitochondrial dysfunction, decreased energy production, and increased generation of reactive oxygen species (ROS). Although numerous cell signaling pathways are activated when cells are injured, the ataxia telangiectasia mutant (ATM) protein has emerged as a major regulator of the response to both mitochondrial dysfunction and nuclear DNA double-strand breaks (DSBs). Because mitochondrial dysfunction is often a response to excessive DNA damage, it has been difficult to determine whether nuclear and/or mitochondrial DNA DSBs activate ATM independent of mitochondrial dysfunction...
October 2014: Free Radical Biology & Medicine
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