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https://www.readbyqxmd.com/read/27915381/regulation-of-non-homologous-end-joining-via-post-translational-modifications-of-components-of-the-ligation-step
#1
REVIEW
Kristína Durdíková, Miroslav Chovanec
DNA double-strand breaks are the most serious type of DNA damage and non-homologous end joining (NHEJ) is an important pathway for their repair. In Saccharomyces cerevisiae, three complexes mediate the canonical NHEJ pathway, Ku (Ku70/Ku80), MRX (Mre11/Rad50/Xrs2) and DNA ligase IV (Dnl4/Lif1). Mammalian NHEJ is more complex, primarily as a consequence of the fact that more factors are involved in the process, and also because higher chromatin organization and more complex regulatory networks exist in mammals...
December 3, 2016: Current Genetics
https://www.readbyqxmd.com/read/27907109/loss-of-h3k9me3-correlates-with-atm-activation-and-histone-h2ax-phosphorylation-deficiencies-in-hutchinson-gilford-progeria-syndrome
#2
Haoyue Zhang, Linlin Sun, Kun Wang, Di Wu, Mason Trappio, Celeste Witting, Kan Cao
Compelling evidence suggests that defective DNA damage response (DDR) plays a key role in the premature aging phenotypes in Hutchinson-Gilford progeria syndrome (HGPS). Studies document widespread alterations in histone modifications in HGPS cells, especially, the global loss of histone H3 trimethylated on lysine 9 (H3K9me3). In this study, we explore the potential connection(s) between H3K9me3 loss and the impaired DDR in HGPS. When cells are exposed to a DNA-damaging agent Doxorubicin (Dox), double strand breaks (DSBs) are generated that result in the phosphorylation of histone H2A variant H2AX (gammaH2AX) within an hour...
2016: PloS One
https://www.readbyqxmd.com/read/27901115/p53-coordinates-dna-repair-with-nucleotide-synthesis-by-suppressing-pfkfb3-expression-and-promoting-the-pentose-phosphate-pathway
#3
Derek A Franklin, Yizhou He, Patrick L Leslie, Andrey P Tikunov, Nick Fenger, Jeffrey M Macdonald, Yanping Zhang
Activation of p53 in response to DNA damage is essential for tumor suppression. Although previous studies have emphasized the importance of p53-dependent cell cycle arrest and apoptosis for tumor suppression, recent studies have suggested that other areas of p53 regulation, such as metabolism and DNA damage repair (DDR), are also essential for p53-dependent tumor suppression. However, the intrinsic connections between p53-mediated DDR and metabolic regulation remain incompletely understood. Here, we present data suggesting that p53 promotes nucleotide biosynthesis in response to DNA damage by repressing the expression of the phosphofructokinase-2 (PFK2) isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a rate-limiting enzyme that promotes glycolysis...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27884198/use-of-poly-adp-ribose-polymerase-parp-inhibitors-in-cancer-cells-bearing-ddr-defects-the-rationale-for-their-inclusion-in-the-clinic
#4
REVIEW
Aniello Cerrato, Francesco Morra, Angela Celetti
BACKGROUND: DNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects...
November 24, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27863405/identification-of-evolutionarily-conserved-dna-damage-response-genes-that-alter-sensitivity-to-cisplatin
#5
Anna V Gaponova, Alexander Y Deneka, Tim N Beck, Hanqing Liu, Gregory Andrianov, Anna S Nikonova, Emmanuelle Nicolas, Margret B Einarson, Erica A Golemis, Ilya G Serebriiskii
Ovarian, head and neck, and other cancers are commonly treated with cisplatin and other DNA damaging cytotoxic agents. Altered DNA damage response (DDR) contributes to resistance of these tumors to chemotherapies, some targeted therapies, and radiation. DDR involves multiple protein complexes and signaling pathways, some of which are evolutionarily ancient and involve protein orthologs conserved from yeast to humans. To identify new regulators of cisplatin-resistance in human tumors, we integrated high throughput and curated datasets describing yeast genes that regulate sensitivity to cisplatin and/or ionizing radiation...
November 15, 2016: Oncotarget
https://www.readbyqxmd.com/read/27854239/kshv-entry-and-trafficking-in-target-cells-hijacking-of-cell-signal-pathways-actin-and-membrane-dynamics
#6
REVIEW
Binod Kumar, Bala Chandran
Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically associated with human endothelial cell hyperplastic Kaposi's sarcoma and B-cell primary effusion lymphoma. KSHV infection of adherent endothelial and fibroblast cells are used as in vitro models for infection and KSHV enters these cells by host membrane bleb and actin mediated macropinocytosis or clathrin endocytosis pathways, respectively. Infection in endothelial and fibroblast cells is initiated by the interactions between multiple viral envelope glycoproteins and cell surface associated heparan sulfate (HS), integrins (α3β1, αVβ3 and αVβ5), and EphA2 receptor tyrosine kinase (EphA2R)...
November 14, 2016: Viruses
https://www.readbyqxmd.com/read/27852949/transcriptional-gene-silencing-maintained-by-ots1-sumo-protease-requires-a-polymerase-v-dependent-pathway
#7
Lei Liu, Xiaojing Yan, Xiang Xiong Kong, Yiqiang Zhao, Zhizhong Gong, Jing Bo Jin, Yan Guo
The expression of genes with aberrant structure is prevented at both transcriptional- and posttranscriptional-regulation levels. Aberrant gene silencing at posttranscriptional level is well studied, however, it is not well understood how aberrant genes are silenced at transcriptional level. In this study, through genetic screening a transgenic report line that harbors an aberrant gene (35S-LUC, lacking 3'-UTR) and lacks luciferase (LUC) activity, we identify that the SUMO protease OTS1 gene is required for maintaining the silence of the reporter 35S-LUC and an endogenous mutator-like element MULE-F19G14 at transcriptional level, which requires Pol V and DDR complex, but not Pol IV...
November 16, 2016: Plant Physiology
https://www.readbyqxmd.com/read/27852625/stabilization-of-the-metaphase-spindle-by-cdc14-is-required-for-recombinational-dna-repair
#8
María Teresa Villoria, Facundo Ramos, Encarnación Dueñas, Peter Faull, Pedro Rodríguez Cutillas, Andrés Clemente-Blanco
Cells are constantly threatened by multiple sources of genotoxic stress that cause DNA damage. To maintain genome integrity, cells have developed a coordinated signalling network called DNA damage response (DDR). While multiple kinases have been thoroughly studied during DDR activation, the role of protein dephosphorylation in the damage response remains elusive. Here, we show that the phosphatase Cdc14 is essential to fulfil recombinational DNA repair in budding yeast. After DNA double-strand break (DSB) generation, Cdc14 is transiently released from the nucleolus and activated...
November 16, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27836727/modulation-of-the-dna-damage-response-during-the-life-cycle-of-human-papillomaviruses
#9
REVIEW
Daniel C Anacker, Cary A Moody
Human papillomavirus (HPV) is the most common sexually transmitted viral infection. Infection with certain types of HPV pose a major public health risk as these types are associated with multiple human cancers, including cervical cancer, other anogenital malignancies and an increasing number of head and neck cancers. The HPV life cycle is closely tied to host cell differentiation with late viral events such as structural gene expression and viral genome amplification taking place in the upper layers of the stratified epithelium...
November 8, 2016: Virus Research
https://www.readbyqxmd.com/read/27822407/exosomes-mediate-micrornas-transfer-in-breast-cancer-chemoresistance-regulation
#10
REVIEW
Juliana Carvalho Santos, Marcelo Lima Ribeiro, Luis Otávio Sarian, Manoela Marques Ortega, Sophie Françoise Derchain
Breast cancer is the most common and fatal type of cancer in women worldwide due to the metastatic process and resistance to treatment. Despite advances in molecular knowledge, little is known regarding resistance to chemotherapy. One highlighted aspect is the DNA damage response (DDR) pathway that is activated upon genotoxic damage, controlling the cell cycle arrest or DNA repair activation. Recently, studies have showed that cancer stem cells (CSCs) could promote chemoresistance through DDR pathway. Furthermore, it is known that the epithelial-mesenchymal transition (EMT) can generate cells with CSCs characteristics and therefore regulate the chemoresistance process...
2016: American Journal of Cancer Research
https://www.readbyqxmd.com/read/27821802/role-of-dna-repair-machinery-and-p53-in-the-testicular-germ-cell-cancer-a-review
#11
REVIEW
Francesco Jacopo Romano, Sabrina Rossetti, Vincenza Conteduca, Giuseppe Schepisi, Carla Cavaliere, Rossella Di Franco, Elvira Lamantia, Luigi Castaldo, Flavia Nocerino, Gianluca Ametrano, Francesca Cappuccio, Gabriella Malzone, Micaela Montanari, Daniela Vanacore, Vincenzo Quagliariello, Raffaele Piscitelli, Maria Filomena Pepe, Massimiliano Berretta, Carmine D'Aniello, Sisto Perdonà, Paolo Muto, Gerardo Botti, Gennaro Ciliberto, Bianca Maria Veneziani, Francesco De Falco, Piera Maiolino, Michele Caraglia, Maurizio Montella, Ugo De Giorgi, Gaetano Facchini
Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate"...
November 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27812882/induction-and-detection-of-oncogene-induced-cellular-senescence-in-drosophila
#12
Mai Nakamura, Tatsushi Igaki
Cellular senescence is induced by various cellular stresses, including activation of the Ras oncogene. In Drosophila imaginal epithelia, clones of cells expressing oncogenic Ras (Ras(V12)) show several markers of cellular senescence, such as elevation of SA-β-gal activity, upregulation of the Cdk inhibitor Dacapo (Dap), and heterochromatinization. However, these cells do not undergo cell cycle arrest or exhibit a DNA damage response (DDR), cellular hypertrophy, or a senescence-associated secretory phenotype (SASP), other essential markers of cellular senescence...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27812868/detection-of-dysfunctional-telomeres-in-oncogene-induced-senescence
#13
Priyanka L Patel, Utz Herbig
Expressing oncogenes in normal somatic human cells leads to cellular senescence after just a few cell division cycles. In cells that are more resistant to culture stresses, such as human dermal fibroblasts, this oncogene-induced senescence (OIS) is a result of a DNA damage response (DDR) that is activated due to the formation of DNA lesions at both non-telomeric and telomeric DNA sequences. DNA lesions can be visualized as DDR foci by immunofluorescence microscopy using antibodies against a number of DDR factors, including ϒ-H2AX and 53BP1...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27802094/mcm8-and-mcm9-nucleotide-variants-in-women-with-primary-ovarian-insufficiency
#14
Swapna Desai, Michelle Wood-Trageser, Jelena Matic, Jaqueline Chipkin, Huaiyang Jiang, Anne Bachelot, Jerome Dulon, Cinzia Sala, Caterina Barbieri, Massimiliano Cocca, Daniela Toniolo, Touraine Philippe, Selma Witchel, Aleksandar Rajkovic
OBJECTIVE: To assess the frequency of variants, including biallelic pathogenic variants, in MCM8 and MCM9, other genes related to MCM8/9 and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). DESIGN: MCM8, MCM9 and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. SETTING: Academic research institution Participants: All were diagnosed with POI prior to the age of 40 and presented with elevated FSH levels...
November 1, 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27797083/the-use-of-laser-microirradiation-to-investigate-the-roles-of-cohesins-in-dna-repair
#15
Xiangduo Kong, Alexander R Ball, Kyoko Yokomori
In addition to their mitotic and transcriptional functions, cohesin plays critical roles in DNA damage response (DDR) and repair. Specifically, cohesin promotes homologous recombination (HR) repair of DNA double-strand breaks (DSBs), which is conserved from yeast to humans, and is a critical effector of ATM/ATR DDR kinase-mediated checkpoint control in mammalian cells. Optical laser microirradiation has been instrumental in revealing the damage site-specific functions of cohesin and, more recently, uncovering the unique role of cohesin-SA2, one of the two cohesin complexes uniquely present in higher eukaryotes, in DNA repair in human cells...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27785368/ercc1-and-telomere-status-in-breast-tumours-treated-with-neoadjuvant-chemotherapy-and-their-association-with-patient-prognosis
#16
Mathilde Gay-Bellile, Pierre Romero, Anne Cayre, Lauren Véronèse, Maud Privat, Shalini Singh, Patricia Combes, Fabrice Kwiatkowski, Catherine Abrial, Yves-Jean Bignon, Philippe Vago, Frédérique Penault-Llorca, Andreï Tchirkov
Dysfunctional telomeres and DNA damage repair (DDR) play important roles in cancer progression. Studies have reported correlations between these factors and tumour aggressiveness and clinical outcome in breast cancer. We studied the characteristics of telomeres and expression of ERCC1, a protein involved in a number of DNA repair pathways and in telomere homeostasis, to assess their prognostic value, alone or in combination, in 90 residual breast tumours after treatment with neoadjuvant chemotherapy (NCT). ERCC1 status was investigated at different molecular levels (protein and gene expression and gene copy-number variations) by immunohistochemistry, qRT-PCR and quantitative multiplex fluorescent-PCR (QMF-PCR)...
October 2016: Journal of Pathology. Clinical Research
https://www.readbyqxmd.com/read/27782108/whole-exome-sequencing-of-finnish-hereditary-breast-cancer-families
#17
Kirsi Määttä, Tommi Rantapero, Anna Lindström, Matti Nykter, Minna Kankuri-Tammilehto, Satu-Leena Laasanen, Johanna Schleutker
A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls...
October 26, 2016: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27775084/tumour-growth-environment-modulates-chk1-signalling-pathways-and-chk1-inhibitor-sensitivity
#18
Andrew J Massey
Clinical development of Chk1 inhibitors is currently focussed on evaluating activity as monotherapy and as potentiators of chemotherapy. To aid translation of pre-clinical studies, we sought to understand the effects of the tumour growth environment on Chk1 signalling and sensitivity to small molecule Chk1 inhibition. Spheroid culture altered Chk1 signalling to a more xenograft like state but decreased sensitivity to Chk1 inhibition. Growth in low serum did not alter DDR signalling but increased the sensitivity of A2058 and U2OS tumour cells to Chk1 inhibition...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27770701/the-rb-binding-domain-of-hpv31-e7-is-required-to-maintain-high-levels-of-dna-repair-factors-in-infected-cells
#19
Bryan A Johnson, Heather L Aloor, Cary A Moody
Human papillomaviruses (HPV) exhibit constitutive activation of ATM and ATR DNA damage response (DDR) pathways, which are required for productive viral replication. Expression of HPV31 E7 alone is sufficient to activate the DDR through an unknown mechanism. Here, we demonstrate that the E7 Rb binding domain is required to increase levels of many DDR proteins, including ATM, Chk2, Chk1, the MRN components MRE11, Rad50, and NBS1, as well as the homologous recombination repair proteins BRCA1 and Rad51. Interestingly, we have found that the increase in these DNA repair proteins does not occur solely at the level of transcription, but that E7 broadly increases the half-life of these DDR factors, a phenotype that is lost in the E7 Rb binding mutant...
October 19, 2016: Virology
https://www.readbyqxmd.com/read/27769272/erratum-to-a-novel-mathematical-model-of-atm-p53-nf-%C3%AE%C2%BAb-pathways-points-to-the-importance-of-the-ddr-switch-off-mechanisms
#20
Katarzyna Jonak, Monika Kurpas, Katarzyna Szoltysek, Patryk Janus, Agata Abramowicz, Krzysztof Puszynski
No abstract text is available yet for this article.
October 21, 2016: BMC Systems Biology
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