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https://www.readbyqxmd.com/read/28525740/rnf8-and-ube2s-dependent-ubiquitin-lysine-11-linkage-modification-in-response-to-dna-damage
#1
Atanu Paul, Bin Wang
Ubiquitin modification of proteins plays pivotal roles in the cellular response to DNA damage. Given the complexity of ubiquitin conjugation due to the formation of poly-conjugates of different linkages, functional roles of linkage-specific ubiquitin modification at DNA damage sites are largely unclear. We identify that Lys11-linkage ubiquitin modification occurs at DNA damage sites in an ATM-dependent manner, and ubiquitin-modifying enzymes, including Ube2S E2-conjugating enzyme and RNF8 E3 ligase, are responsible for the assembly of Lys11-linkage conjugates on damaged chromatin, including histone H2A/H2AX...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28506460/mechanisms-of-ubiquitin-nucleosome-recognition-and-regulation-of-53bp1-chromatin-recruitment-by-rnf168-169-and-rad18
#2
Qi Hu, Maria Victoria Botuyan, Gaofeng Cui, Debiao Zhao, Georges Mer
The protein 53BP1 plays a central regulatory role in DNA double-strand break repair. 53BP1 relocates to chromatin by recognizing RNF168-mediated mono-ubiquitylation of histone H2A Lys15 in the nucleosome core particle dimethylated at histone H4 Lys20 (NCP-ubme). 53BP1 relocation is terminated by ubiquitin ligases RNF169 and RAD18 via unknown mechanisms. Using nuclear magnetic resonance (NMR) spectroscopy and biochemistry, we show that RNF169 bridges ubiquitin and histone surfaces, stabilizing a pre-existing ubiquitin orientation in NCP-ubme to form a high-affinity complex...
May 18, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28498430/uva-induced-upregulation-of-progerin-suppresses-53bp1%C3%A2-mediated-nhej-dsb-repair-in-human-keratinocytes-via-progerin-lamin%C3%A2-a-complex-formation
#3
Xin Huang, Yun Pan, Di Cao, Sheng Fang, Kun Huang, Jin Chen, Aijun Chen
Ultraviolet (UV) radiation is the primary risk factor underlying photoaging and photocarcinogenesis. Mounting research has focused on the role of DNA damage response pathways in UV-induced double-strand break (DSB) repair. In the present study, we hypothesized that UVA-induced aberrant progerin upregulation may adversely affect p53-binding protein 1 (53BP1)-mediated non-homologous end joining (NHE) DSB repair in human keratinocytes. Basal cell carcinoma (BCC) tumors and matching normal skin tissue were sampled (n=200) to investigate whether human keratinocytes display dysregulated progerin expression as a function of advancing age and BCC status...
April 26, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28492345/the-focinator-v2-0-graphical-interface-four-channels-colocalization-analysis-and-cell-phase-identification
#4
Sebastian Oeck, Nathalie M Malewicz, Sebastian Hurst, Klaudia Al-Refae, Adam Krysztofiak, Verena Jendrossek
The quantitative analysis of foci plays an important role in various cell biological methods. In the fields of radiation biology and experimental oncology, the effect of ionizing radiation, chemotherapy or molecularly targeted drugs on DNA damage induction and repair is frequently performed by the analysis of protein clusters or phosphorylated proteins recruited to so called repair foci at DNA damage sites, involving for example γ-H2A.X, 53BP1 or RAD51. We recently developed "The Focinator" as a reliable and fast tool for automated quantitative and qualitative analysis of nuclei and DNA damage foci...
May 11, 2017: Radiation Research
https://www.readbyqxmd.com/read/28481984/the-dna-damage-response-ddr-is-induced-by-the-c9orf72-repeat-expansion-in-amyotrophic-lateral-sclerosis
#5
Manal A Farg, Anna Konopka, Kai Ying Soo, Daisuke Ito, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease affecting motor neurons. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide. The C9orf72 repeat expansion undergoes repeat-associated non-ATG (RAN) translation to produce five dipeptide repeat proteins (DRPs), including poly(GR) and poly(PR). Whilst it remains unclear how mutations in C9orf72 lead to neurodegeneration in ALS/FTD, dysfunction to the nucleolus and R loop formation are implicated as pathogenic mechanisms...
May 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28475402/dna-repair-genes-paxip1-and-tp53bp1-expression-is-associated-with-breast-cancer-prognosis
#6
Giuliana De Gregoriis, Juliene Antonio Ramos, Priscila Valverde Fernandes, Giselle Maria Vignal, Rafael Canfield Brianese, Dirce Maria Carraro, Alvaro N Monteiro, Claudio Struchiner, Guilherme Suarez-Kurtz, Rosane Vianna-Jorge, Marcelo Alex de Carvalho
Despite remarkable advances in diagnosis, prognosis and treatment, advanced or recurrent breast tumors have limited therapeutic approaches. Many treatment strategies try to explore the limitations of DNA damage response (DDR) in tumor cells to selectively eliminate them. BRCT (BRCA1 Carboxy-Terminal) domains are present in a superfamily of proteins involved in cell cycle checkpoints and the DDR. Tandem BRCT domains (tBRCT) represent a distinct class of these domains. We investigated the expression profile of seven tBRCT genes (BARD1, BRCA1, LIG4, ECT2, MDC1, PAXIP1/PTIP and TP53BP1) in breast cancer specimens and observed a high correlation between PAXIP1 and TP53BP1 gene expression in tumor samples...
May 5, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28447610/parp3-is-a-promoter-of-chromosomal-rearrangements-and-limits-g4-dna
#7
Tovah A Day, Jacob V Layer, J Patrick Cleary, Srijoy Guha, Kristen E Stevenson, Trevor Tivey, Sunhee Kim, Anna C Schinzel, Francesca Izzo, John Doench, David E Root, William C Hahn, Brendan D Price, David M Weinstock
Chromosomal rearrangements are essential events in the pathogenesis of both malignant and nonmalignant disorders, yet the factors affecting their formation are incompletely understood. Here we develop a zinc-finger nuclease translocation reporter and screen for factors that modulate rearrangements in human cells. We identify UBC9 and RAD50 as suppressors and 53BP1, DDB1 and poly(ADP)ribose polymerase 3 (PARP3) as promoters of chromosomal rearrangements across human cell types. We focus on PARP3 as it is dispensable for murine viability and has druggable catalytic activity...
April 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/28445939/epigenetic-therapy-with-inhibitors-of-histone-methylation-suppresses-dna-damage-signaling-and-increases-glioma-cell-radiosensitivity
#8
Ozge Gursoy-Yuzugullu, Chelsea Carman, Rodolfo Bortolozo Serafim, Marios Myronakis, Valeria Valente, Brendan D Price
Radiation therapy is widely used to treat human malignancies, but many tumor types, including gliomas, exhibit significant radioresistance. Radiation therapy creates DNA double-strand breaks (DSBs), and DSB repair is linked to rapid changes in epigenetic modifications, including increased histone methylation. This increased histone methylation recruits DNA repair proteins which can then alter the local chromatin structure and promote repair. Consequently, combining inhibitors of specific histone methyltransferases with radiation therapy may increase tumor radiosensitivity, particularly in tumors with significant therapeutic resistance...
April 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28442502/ribonucleotide-reductase-large-subunit-rrm1-as-a-novel-therapeutic-target-in-multiple-myeloma
#9
Morihiko Sagawa, Hiroto Ohguchi, Takeshi Harada, Mehmet K Samur, Yu-Tzu Tai, Nikhil C Munshi, Masahiro Kizaki, Teru Hideshima, Kenneth C Anderson
Purpose: To investigate the biologic and clinical significance of ribonucleotide reductase (RR) in multiple myeloma (MM). <p>Experimental Design: We assessed the impact of RR expression on patient outcome in MM. We then characterized the effect of genetic and pharmacological inhibition of RRM1 on MM growth and survival using siRNA and clofarabine (CLO), respectively, both in vitro and in vivo mouse xenograft model.</p> <p>Results: Newly diagnosed MM patients with higher RRM1 expression have shortened survival...
April 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28415769/aurora-kinase-b-dependent-phosphorylation-of-53bp1-is-required-for-resolving-merotelic-kinetochore-microtubule-attachment-errors-during-mitosis
#10
Haibo Wang, Bin Peng, Raj K Pandita, David A Engler, Risë K Matsunami, Xingzhi Xu, Pavana M Hegde, Brian E Butler, Tej K Pandita, Sankar Mitra, Bo Xu, Muralidhar L Hegde
Defects in resolving kinetochore-microtubule attachment mistakes during mitosis is linked to chromosome instability associated with carcinogenesis as well as resistance to cancer therapy. Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. Furthermore, 53BP1 staining normally localized on the outer kinetochore, extended to the whole kinetochore when it is merotelically-attached, in concert with mitotic centromere-associated kinesin...
March 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414200/combining-53bp1-with-brca1-as-a-biomarker-to-predict-the-sensitivity-of-poly-adp-ribose-polymerase-parp-inhibitors
#11
Zhong-Min Yang, Xue-Mei Liao, Yi Chen, Yan-Yan Shen, Xin-Ying Yang, Yi Su, Yi-Ming Sun, Ying-Lei Gao, Jian Ding, Ao Zhang, Jin-Xue He, Ze-Hong Miao
Over half of patients with BRCA1-deficient cancers do not respond to treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we report that a combination of 53BP1 and BRCA1 may serve as a biomarker of PARP inhibitor sensitivity. Based on the mRNA levels of four homologous recombination repair (HR) genes and PARP inhibitor sensitivity, we selected BRCA1-deficient MDA-MB-436 cells to conduct RNA interference. Reducing expression of 53BP1, but not the other three HR genes, was found to lower simmiparib sensitivity...
April 17, 2017: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/28412751/poly-adp-ribose-polymerase-inhibitor-an-effective-radiosensitizer-in-lung-and-pancreatic-cancers
#12
Kedar Hastak, Steven Bhutra, Renate Parry, James M Ford
The development of stereotactic body radiation therapy (SBRT) has revolutionized radiation therapy for lung cancers and is an emerging treatment option for pancreatic cancers. However, there are many questions on how to optimize its use in chemoradiotherapy. The most relevant addition to radiotherapy regimens are inhibitors of DNA repair and DNA damage response pathways. One such class of agents are inhibitors of poly (ADP-ribose) polymerase (PARP). In this study we examined the effects of the PARP inhibitor LT626 in combination with ionizing radiation in lung and pancreatic cancers...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28406750/sirtuins-and-dna-damage-repair-sirt7-comes-to-play
#13
REVIEW
Berta N Vazquez, Joshua K Thackray, Lourdes Serrano
Aging is characterized by a cumulative loss of genome integrity, which involves chromatin reorganization, transcriptional dysregulation and the accumulation of DNA damage. Sirtuins participate in the protection against these aging processes by promoting genome homeostasis in response to cellular stress. We recently reported that SirT7(-/-) mice suffer from partial embryonic lethality and a progeroid like phenotype. At the cellular level, SIRT7 depletion results in the impaired repair of DNA double-strand breaks (DSBs), one the most dangerous DNA lesions, leading to genome instability...
March 4, 2017: Nucleus
https://www.readbyqxmd.com/read/28406400/the-rnf168-paralog-rnf169-defines-a-new-class-of-ubiquitylated-histone-reader-involved-in-the-response-to-dna-damage
#14
Julianne Kitevski-LeBlanc, Amélie Fradet-Turcotte, Predrag Kukic, Marcus D Wilson, Guillem Portella, Tairan Yuwen, Stephanie Panier, Shili Duan, Marella D Canny, Hugo van Ingen, Cheryl H Arrowsmith, John L Rubinstein, Michele Vendruscolo, Daniel Durocher, Lewis E Kay
Site-specific histone ubiquitylation plays a central role in orchestrating the response to DNA double-strand breaks (DSBs). DSBs elicit a cascade of events controlled by the ubiquitin ligase RNF168, which promotes the accumulation of repair factors such as 53BP1 and BRCA1 on the chromatin flanking the break site. RNF168 also promotes its own accumulation, and that of its paralog RNF169, but how they recognize ubiquitylated chromatin is unknown. Using methyl-TROSY solution NMR spectroscopy and molecular dynamics simulations, we present an atomic resolution model of human RNF169 binding to a ubiquitylated nucleosome, and validate it by electron cryomicroscopy...
April 13, 2017: ELife
https://www.readbyqxmd.com/read/28398700/differential-requirements-for-dna-repair-proteins-in-immortalized-cell-lines-using-alternative-lengthening-of-telomere-mechanisms
#15
Alaina R Martinez, Zeenia Kaul, Jeffrey D Parvin, Joanna Groden
Cancer cells require telomere maintenance to enable uncontrolled growth. Most often telomerase is activated, although a subset of human cancers are telomerase-negative and depend on recombination-based mechanisms known as ALT (Alternative Lengthening of Telomeres). ALT depends on proteins that are essential for homologous recombination, including BLM and the MRN complex, to extend telomeres. This study surveyed the requirement for requisite homologous recombination proteins, yet to be studied in human ALT cell lines, by protein depletion using RNA interference...
April 11, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28397142/mutations-in-the-tp53-gene-affected-recruitment-of-53bp1-protein-to-dna-lesions-but-level-of-53bp1-was-stable-after-%C3%AE-irradiation-that-depleted-mdc1-protein-in-specific-tp53-mutants
#16
Jana Suchánková, Soňa Legartová, Eva Ručková, Bořivoj Vojtěšek, Stanislav Kozubek, Eva Bártová
53BP1 is a very well-known protein that is recruited to DNA lesions. The focal accumulation of p53 binding protein, 53BP1, is a main feature indicating the repair of spontaneous or irradiation-induced foci (IRIF). Thus, here, we addressed the question of whether mutations in the TP53 gene, which often affect the level of p53 protein, can change the recruitment of 53BP1 to γ- or UVA-irradiated chromatin. In various TP53 mutants, we observed a distinct accumulation of 53BP1 protein to UV-induced DNA lesions: in R273C mutants, 53BP1 appeared transiently at DNA lesions, during 10-30 min after irradiation; the mutation R282W was responsible for accumulation of 53BP1 immediately after UVA-damage; and in L194F mutants, the first appearance of 53BP1 protein at the lesions occurred during 60-70 min...
April 10, 2017: Histochemistry and Cell Biology
https://www.readbyqxmd.com/read/28383788/replication-stress-dna-damage-signalling-and-cytomegalovirus-infection-in-human-medulloblastomas
#17
Jiri Bartek, Olesja Fornara, Joanna Maria Merchut-Maya, Apolinar Maya-Mendoza, Afshar Rahbar, Giuseppe Stragliotto, Helle Broholm, Mikael Svensson, Astrid Sehested, Cecilia Söderberg Naucler, Jiri Bartek, Jirina Bartkova
Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection...
April 6, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28381412/the-ddr-at-telomeres-lacking-intact-shelterin-does-not-require-substantial-chromatin-decompaction
#18
Leonid A Timashev, Hazen Babcock, Xiaowei Zhuang, Titia de Lange
Telomeres are protected by shelterin, a six-subunit protein complex that represses the DNA damage response (DDR) at chromosome ends. Extensive data suggest that TRF2 in shelterin remodels telomeres into the t-loop structure, thereby hiding telomere ends from double-stranded break repair and ATM signaling, whereas POT1 represses ATR signaling by excluding RPA. An alternative protection mechanism was suggested recently by which shelterin subunits TRF1, TRF2, and TIN2 mediate telomeric chromatin compaction, which was proposed to minimize access of DDR factors...
March 15, 2017: Genes & Development
https://www.readbyqxmd.com/read/28373429/dna-double-strand-breaks-induced-byfractionated-neutron-beam-irradiation-for-boron-neutron-capture-therapy
#19
Yuko Kinashi, Natsuya Yokomizo, Sentaro Takahashi
AIM: To use the 53BP1 foci assay to detect DNA double-strand breaks induced by fractionated neutron beam irradiation of normal cells. MATERIALS AND METHODS: The Kyoto University Research Reactor heavy-water facility and gamma-ray irradiation system were used as experimental radiation sources. After fixation of Chinese Hamster Ovary cells with 3.6% formalin, immunofluorescence staining was performed. Number and size of foci were analyzed using ImageJ software. RESULTS: Fractionated neutron irradiation induced 25% fewer 53BP1 foci than single irradiation at the same dose...
April 2017: Anticancer Research
https://www.readbyqxmd.com/read/28359030/increase-of-dna-damage-and-alteration-of-the-dna-damage-response-in-myelodysplastic-syndromes-and-acute-myeloid-leukemias
#20
Henning D Popp, Nicole Naumann, Susanne Brendel, Thomas Henzler, Christel Weiss, Wolf-Karsten Hofmann, Alice Fabarius
Increased DNA damage and alteration of the DNA damage response (DDR) are critical features of genetic instability presumably implicated in pathogenesis of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). We used immunofluorescence staining of γH2AX and 53BP1 for analyzing DNA double-strand breaks (DSB) in MDS and AML cell lines, in CD34+ selected cells of normal and MDS bone marrow (including three cases of chronic myelomonocytic leukemias) and in blasts of AML bone marrow. In addition, we screened for activation of the DDR by immunoblotting of p-ATM, p-ATR, p-CHK1, p-CHK2 and p-TP53...
March 21, 2017: Leukemia Research
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