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https://www.readbyqxmd.com/read/28718433/mitotic-dna-damage-response-at-the-crossroads-of-structural-and-numerical-cancer-chromosome-instabilities
#1
REVIEW
Samuel F Bakhoum, Lilian Kabeche, Duane A Compton, Simon N Powell, Holger Bastians
DNA double-strand breaks (DSBs) prevent cells from entering mitosis allowing cells to repair their genomic damage. Little is known about the response to DSBs once cells have already committed to mitosis. Here, we review the genome-protective role of the mitotic DNA damage response (DDR) and evidence suggesting that its untimely activation induces chromosome segregation errors and paradoxically undermines genomic integrity. In contrast to normal cells, cancer cells coopt this pathway to propagate structural and numerical chromosomal instabilities...
March 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28713336/development-and-use-of-a-real-time-quantitative-pcr-method-for-detecting-and-quantifying-equol-producing-bacteria-in-human-faecal-samples-and-slurry-cultures
#2
Lucía Vázquez, Lucía Guadamuro, Froilán Giganto, Baltasar Mayo, Ana B Flórez
This work introduces a novel real-time quantitative PCR (qPCR) protocol for detecting and quantifying equol-producing bacteria. To this end, two sets of primers targeting the dihydrodaidzein reductase (ddr) and tetrahydrodaidzein reductase (tdr) genes, which are involved in the synthesis of equol, were designed. The primers showed high specificity and sensitivity when used to examine DNA from control bacteria, such as Slackia isoflavoniconvertens, Slackia equolifaciens, Asaccharobacter celatus, Adlercreutzia equolifaciens, and Enterorhabdus mucosicola...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28707218/the-dna-damage-response-pathway-in-normal-hematopoiesis-and-malignancies
#3
REVIEW
Domenico Delia, Shuki Mizutani
In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations...
July 13, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28687272/interstrand-crosslink-repair-as-a-target-for-hdac-inhibition
#4
REVIEW
Teodora Nikolova, Nicole Kiweler, Oliver H Krämer
DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network...
July 4, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28682452/mitochondrial-dysfunction-and-potential-anticancer-therapy
#5
REVIEW
Matilde E Lleonart, Robert Grodzicki, Dmitri M Graifer, Alex Lyakhovich
Mitochondrial dysfunction (MDF) has been identified as an important factor in various diseases ranging from neurological disorders, to diseases of the cardiovascular system and metabolic syndromes. MDF was also found in cancer as well as in cancer predisposition syndromes with defective DNA damage response (DDR) machinery. Moreover, a recent highlight arises from the detection of MDF in eukaryotic cells upon treatment with antibiotics. In this review, we focus on recent studies of MDF in pathological conditions with a particular emphasis on the effects of various classes of antibiotics on mitochondria...
July 6, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28676216/functional-analysis-of-discoidin-domain-receptor-2-mutation-and-expression-in-squamous-cell-lung-cancer
#6
Naomi Kobayashi-Watanabe, Akemi Sato, Tatsuro Watanabe, Tomonori Abe, Chiho Nakashima, Eisaburo Sueoka, Shinya Kimura, Naoko Sueoka-Aragane
OBJECTIVES: Discoidin domain receptor (DDR) 2 mutations have recently been reported to be candidate targets of molecular therapy in lung squamous cell carcinoma (SQCC). However, the status of DDR2 expression and mutations, as well as their precise roles in lung SQCC, have not been clarified. We here report DDR2 mutation and expression status in clinical samples and its role of lung SQCC. MATERIALS AND METHODS: We investigated DDR2 expression and mutation status in 44 human clinical samples and 7 cell lines...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28669341/jq1-a-bet-inhibitor-synergizes-with-cisplatin-and-induces-apoptosis-in-highly-chemoresistant-malignant-pleural-mesothelioma-cells
#7
Ilaria Zanellato, Donato Colangelo, Domenico Osella
Malignant pleural mesothelioma (MPM) is an asbestos-associated tumor with poor prognosis and few therapeutic options. JQ1, a selective antagonist of BRD4, modulates transcription of oncogenes, including MPM chemoresistance-associated c-Myc and Fra-1. We investigated if JQ1 could enhance the efficacy of cisplatin against MPM. The antiproliferative activity of cisplatin in combination with JQ1 was assessed on MPM cell lines representative of the cellular phenotypes of this tumor (epithelioid, sarcomatoid and biphasic), and on one cisplatin-resistant sub-line (established in our laboratory)...
June 23, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28668129/what-combined-measurements-from-structures-and-imaging-tell-us-about-dna-damage-responses
#8
Chris A Brosey, Zamal Ahmed, Susan P Lees-Miller, John A Tainer
DNA damage outcomes depend upon the efficiency and fidelity of DNA damage responses (DDRs) for different cells and damage. As such, DDRs represent tightly regulated prototypical systems for linking nanoscale biomolecular structure and assembly to the biology of genomic regulation and cell signaling. However, the dynamic and multifunctional nature of DDR assemblies can render elusive the correlation between the structures of DDR factors and specific biological disruptions to the DDR when these structures are altered...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28666126/telomere-length-determines-terra-and-r-loop-regulation-through-the-cell-cycle
#9
Marco Graf, Diego Bonetti, Arianna Lockhart, Kamar Serhal, Vanessa Kellner, André Maicher, Pascale Jolivet, Maria Teresa Teixeira, Brian Luke
Maintenance of a minimal telomere length is essential to prevent cellular senescence. When critically short telomeres arise in the absence of telomerase, they can be repaired by homology-directed repair (HDR) to prevent premature senescence onset. It is unclear why specifically the shortest telomeres are targeted for HDR. We demonstrate that the non-coding RNA TERRA accumulates as HDR-promoting RNA-DNA hybrids (R-loops) preferentially at very short telomeres. The increased level of TERRA and R-loops, exclusively at short telomeres, is due to a local defect in RNA degradation by the Rat1 and RNase H2 nucleases, respectively...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28662958/targeting-atr-in-cancer-medicine
#10
REVIEW
Raghav Sundar, Jessica Brown, Alvaro Ingles Russo, Timothy A Yap
DNA damage occurs continually through various intrinsic and extrinsic mechanisms such as ultraviolet radiation, smoking, reactive oxygen species, and errors during replication. The cellular DNA damage response (DDR) comprises signaling networks that regulate a spectrum of processes, including cell cycle progression, which enable DNA repair to occur. Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and rad3-related (ATR) kinase are 2 key regulators of the DDR cell cycle checkpoints. ATR plays an essential role in the repair of replication-associated DNA damage, while ATM is activated by DNA double-strand breaks...
May 17, 2017: Current Problems in Cancer
https://www.readbyqxmd.com/read/28654754/potential-strategies-to-target-protein-protein-interactions-in-the-dna-damage-response-and-repair-pathways
#11
Naoaki Fujii
This review article discusses some insights about generating novel mechanistic inhibitors of the DNA damage response and repair (DDR) pathways by focusing on protein-protein interactions (PPIs) of the key DDR components. General requirements for PPI strategies, such as selecting the target PPI site on the basis of its functionality, are discussed first. Next, on the basis of functional rationale and biochemical feasibility to identify a PPI inhibitor, 26 PPIs in DDR pathways (BER, MMR, NER, NHEJ, HR, TLS, and ICL repair) are specifically discussed for inhibitor discovery to benefit cancer therapies using a DNA-damaging agent...
July 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28652169/oncogene-induced-senescence-and-its-evasion-in-a-mouse-model-of-thyroid-neoplasia
#12
Roberto Bellelli, Donata Vitagliano, Giorgia Federico, Pina Marotta, Anna Tamburrino, Paolo Salerno, Orlando Paciello, Serenella Papparella, Jeffrey A Knauf, James A Fagin, Samuel Refetoff, Giancarlo Troncone, Massimo Santoro
Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF...
June 23, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28649409/bacillus-subtilis-utilizes-the-dna-damage-response-to-manage-multicellular-development
#13
Kevin Gozzi, Carly Ching, Srinand Paruthiyil, Yinjuan Zhao, Veronica Godoy-Carter, Yunrong Chai
Bacteria switch between free-living and a multicellular state, known as biofilms, in response to cellular and environmental cues. It is important to understand how these cues influence biofilm development as biofilms are not only ubiquitous in nature but are also causative agents of infectious diseases. It is often believed that any stress triggers biofilm formation as a means of bacterial protection. In this study, we propose a new mechanism for how cellular and environmental DNA damage may influence biofilm formation...
2017: NPJ Biofilms and Microbiomes
https://www.readbyqxmd.com/read/28648781/pp2a-controls-genome-integrity-by-integrating-nutrient-sensing-and-metabolic-pathways-with-the-dna-damage-response
#14
Elisa Ferrari, Christopher Bruhn, Marta Peretti, Corinne Cassani, Walter Vincenzo Carotenuto, Mohamed Elgendy, Ghadeer Shubassi, Chiara Lucca, Rodrigo Bermejo, Mario Varasi, Saverio Minucci, Maria Pia Longhese, Marco Foiani
Mec1(ATR) mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A...
June 12, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28642363/nuclear-phosphorylated-dicer-processes-double-stranded-rna-in-response-to-dna-damage
#15
Kaspar Burger, Margarita Schlackow, Martin Potts, Svenja Hester, Shabaz Mohammed, Monika Gullerova
The endoribonuclease Dicer is a key component of the human RNA interference pathway and is known for its role in cytoplasmic microRNA production. Recent findings suggest that noncanonical Dicer generates small noncoding RNA to mediate the DNA damage response (DDR). Here, we show that human Dicer is phosphorylated in the platform-Piwi/Argonaute/Zwille-connector helix cassette (S1016) upon induction of DNA damage. Phosphorylated Dicer (p-Dicer) accumulates in the nucleus and is recruited to DNA double-strand breaks...
June 22, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28640660/chromosome-territory-relocation-paradigm-during-dna-damage-response-some-insights-from-molecular-biology-to-physics
#16
Sarosh N Fatakia, Mugdha Kulashreshtha, Ishita S Mehta, Basuthkar J Rao
Among the many facets of DNA damage response (DDR), relocation of chromosome territories (CTs) is most intriguing. We have previously reported that cisplatin induced DDR in human dermal fibroblasts led to relocation of CTs 12, 15 from the nuclear periphery to its interior while CTs 19, 17 repositioned from the interior to its periphery. Studies of CT relocation remain nascent as we begin unraveling the role of key players in DDR to demonstrate its mechanistic basis. Consolidating our recent reports, we argue that γH2AX-signaling leads to enhanced recruitment of nuclear myosin 1 (NM1) to chromatin, which via its motor function, results in CT repositioning...
June 22, 2017: Nucleus
https://www.readbyqxmd.com/read/28634291/rhodium-metalloinsertor-binding-generates-a-lesion-with-selective-cytotoxicity-for-mismatch-repair-deficient-cells
#17
Julie M Bailis, Alyson G Weidmann, Natalie F Mariano, Jacqueline K Barton
The DNA mismatch repair (MMR) pathway recognizes and repairs errors in base pairing and acts to maintain genome stability. Cancers that have lost MMR function are common and comprise an important clinical subtype that is resistant to many standard of care chemotherapeutics such as cisplatin. We have identified a family of rhodium metalloinsertors that bind DNA mismatches with high specificity and are preferentially cytotoxic to MMR-deficient cells. Here, we characterize the cellular mechanism of action of the most potent and selective complex in this family, [Rh(chrysi)(phen)(PPO)](2+) (Rh-PPO)...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28631426/hsp90%C3%AE-regulates-atm-and-nbn-functions-in-sensing-and-repair-of-dna-double-strand-breaks
#18
Rosa Pennisi, Antonio Antoccia, Stefano Leone, Paolo Ascenzi, Alessandra di Masi
The molecular chaperone heat shock protein 90 (Hsp90α) regulates cells proteostasis and mitigates the harmful effects of endogenous and exogenous stressors on the proteome. Indeed, the inhibition of Hsp90α ATPase activity affects the cellular response to ionizing radiation (IR). Although the interplay between Hsp90α and several DNA damage response (DDR) proteins has been reported, its role in the DDR is still unclear. Here, we show that ATM and NBN, but not 53BP1, RAD50, and MRE11, are Hsp90α clients as the Hsp90α inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) induces ATM and NBN polyubiquitination and proteosomal degradation in normal fibroblasts and lymphoblastoid cells lines...
June 20, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28629776/unveiling-the-non-repair-face-of-the-base-excision-repair-pathway-in-rna-processing-a-missing-link-between-dna-repair-and-gene-expression
#19
REVIEW
Giulia Antoniali, Matilde Clarissa Malfatti, Gianluca Tell
The Base Excision Repair (BER) pathway, initially studied as a mere DNA repair pathway, has been later found to be implicated in the expression of cancer related genes in human. For several years, this intricate involvement in apparently different processes represented a mystery, which we now are starting to unveil. The BER handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. Surprisingly, BER pathway involvement in transcriptional regulation, immunoglobulin variability and switch recombination, RNA metabolism and nucleolar function is astonishingly consolidating...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28627136/enhancer-of-rudimentary-homologue-interacts-with-scaffold-attachment-factor-b-at-the-nuclear-matrix-to-regulate-sr-protein-phosphorylation
#20
Sotiria Drakouli, Aggeliki Lyberopoulou, Maria Papathanassiou, Ilias Mylonis, Eleni Georgatsou
Scaffold Attachment Factor B1 (SAFB1) is an integral component of the nuclear matrix of vertebrate cells.It binds to DNA on scaffold/matrix attachment region (S/MAR) elements, to RNA, and to a multitude of different proteins, affecting, as has been extensively substantiated, basic cellular activities such as transcription, splicing and DNA damage repair (DDR). In this study, we show that Enhancer of Rudimentary Homologue (ERH) is a new molecular partner of SAFB1 and its 70% homologous paralogue, Scaffold Attachment Factor B2 (SAFB2)...
June 19, 2017: FEBS Journal
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