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Kamalesh Dattaram Mumbrekar, Satish Rao Bola Sadashiva, Shama Prasada Kabekkodu, Donald Jerard Fernandes, Bejadi Manjunath Vadhiraja, Tomo Suga, Yoshimi Shoji, Fumiaki Nakayama, Takashi Imai, Kapaettu Satyamoorthy
PURPOSE: Heterogeneity in radiation therapy (RT)-induced normal tissue toxicity is observed in 10% of cancer patients, limiting the therapeutic outcomes. In addition to treatment-related factors, normal tissue adverse reactions also manifest from genetic alterations in distinct pathways majorly involving DNA damage-repair genes, inflammatory cytokine genes, cell cycle regulation, and antioxidant response. Therefore, the common sequence variants in these radioresponsive genes might modify the severity of normal tissue toxicity, and the identification of the same could have clinical relevance as a predictive biomarker...
January 1, 2017: International Journal of Radiation Oncology, Biology, Physics
Liu Feng, Wang Wei, Zhang Heng, Han Yantao, Wang Chunbo
REV7 (also known as MAD2L2) is a multifunctional protein involved in DNA damage tolerance, cell cycle regulation, gene expression, and carcinogenesis. Although its expression is reportedly associated with poor prognosis in several kinds of human cancers, the significance of REV7 expression in breast malignancies is unclear. In this study, REV7 was found to be increased in breast cancer. We found that knockdown of REV7 inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of breast cancer cells...
2016: Oncology Research
Dominique Bluteau, Julien Masliah-Planchon, Connor Clairmont, Alix Rousseau, Raphael Ceccaldi, Catherine Dubois d'Enghien, Olivier Bluteau, Wendy Cuccuini, Stéphanie Gachet, Régis Peffault de Latour, Thierry Leblanc, Gérard Socié, André Baruchel, Dominique Stoppa-Lyonnet, Alan D D'Andrea, Jean Soulier
Fanconi anemia (FA) is a recessive genetic disease characterized by congenital abnormalities, chromosome instability, progressive bone marrow failure (BMF), and a strong predisposition to cancer. Twenty FA genes have been identified, and the FANC proteins they encode cooperate in a common pathway that regulates DNA crosslink repair and replication fork stability. We identified a child with severe BMF who harbored biallelic inactivating mutations of the translesion DNA synthesis (TLS) gene REV7 (also known as MAD2L2), which encodes the mutant REV7 protein REV7-V85E...
September 1, 2016: Journal of Clinical Investigation
Audesh Bhat, Zhaojia Wu, Veronica M Maher, J Justin McCormick, Wei Xiao
The spindle assembly checkpoint (SAC) acts as a guardian against cellular threats that may lead to chromosomal missegregation and aneuploidy. Mad2, an anaphase-promoting complex/cyclosome-Cdc20 (APC/C(Cdc20)) inhibitor, has an additional homolog in mammals known as Mad2B, Mad2L2 or Rev7. Apart from its role in Polζ-mediated translesion DNA synthesis and double-strand break repair, Rev7 is also believed to inhibit APC/C by negatively regulating Cdh1. Here we report yet another function of Rev7 in cultured human cells...
2015: Cell Cycle
A M Mongan, N Lynam-Lennon, R Casey, S Maher, G Pidgeon, J V Reynolds, J O'Sullivan
PURPOSE: Oesophageal adenocarcinoma is an exemplar model of obesity-associated cancer. Locally advanced disease is treated with neoadjuvant chemoradiotherapy, and survival rates are highest in patients demonstrating a pathological response following neoadjuvant therapy. Given that 55 % of oesophageal adenocarcinoma patients are obese, uncovering the effect of adipose tissue on radioresponse is clinically relevant. This study investigates if adipose tissue activates genomic instability events in radioresponsive (OE33P) and radioresistant (OE33R) oesophageal cancer cell lines and tumour samples...
June 2016: Clinical & Translational Oncology
Marina Gonçalves Diniz, Jeane de Fatima Correia Silva, Fabricio Tinôco Alvim de Souza, Núbia Braga Pereira, Carolina Cavaliéri Gomes, Ricardo Santiago Gomez
Higher tumor size correlates with poor prognosis and is an independent predictive survival factor in oral squamous cell carcinoma (OSCC) patients. However, the molecular events underlining OSCC tumor evolution are poorly understood. We aimed to investigate if large OSCC tumors show different cell cycle gene transcriptional signature compared to small tumors. Seventeen fresh OSCC tumor samples with different tumor sizes (T) were included in the study. Tumors were from the tongue or from the floor of the mouth, and only three patients were nonsmokers...
December 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Mehdi Pirouz, Ali Rahjouei, Farnaz Shamsi, Kolja Neil Eckermann, Gabriela Salinas-Riester, Claudia Pommerenke, Michael Kessel
The induction and maintenance of pluripotency requires the expression of several core factors at appropriate levels (Oct4, Sox2, Klf4, Prdm14). A subset of these proteins (Oct4, Sox2, Prdm14) also plays crucial roles for the establishment of primordial germ cells (PGCs). Here we demonstrate that the Mad2l2 (MAD2B, Rev7) gene product is not only required by PGCs, but also by pluripotent embryonic stem cells (ESCs), depending on the growth conditions. Mad2l2(-/-) ESCs were unstable in LIF/serum medium, and differentiated into primitive endoderm...
2015: Cell Cycle
Julian E Sale
No abstract text is available yet for this article.
June 12, 2015: EMBO Journal
Koji Hatano, Binod Kumar, Yonggang Zhang, Jonathan B Coulter, Mohammad Hedayati, Brian Mears, Xiaohua Ni, Tarana A Kudrolli, Wasim H Chowdhury, Ronald Rodriguez, Theodore L DeWeese, Shawn E Lupold
MicroRNAs (miRNAs) have been implicated in DNA repair pathways through transcriptional responses to DNA damaging agents or through predicted miRNA regulation of DNA repair genes. We hypothesized that additional DNA damage regulating miRNAs could be identified by screening a library of 810 miRNA mimetics for the ability to alter cellular sensitivity to ionizing radiation (IR). A prostate cancer Metridia luciferase cell model was applied to examine the effects of individual miRNAs on IR sensitivity. A large percentage of miRNA mimetics were found to increase cellular sensitivity to IR, while a smaller percentage were protective...
April 30, 2015: Nucleic Acids Research
Guotai Xu, J Ross Chapman, Inger Brandsma, Jingsong Yuan, Martin Mistrik, Peter Bouwman, Jirina Bartkova, Ewa Gogola, Daniël Warmerdam, Marco Barazas, Janneke E Jaspers, Kenji Watanabe, Mark Pieterse, Ariena Kersbergen, Wendy Sol, Patrick H N Celie, Philip C Schouten, Bram van den Broek, Ahmed Salman, Marja Nieuwland, Iris de Rink, Jorma de Ronde, Kees Jalink, Simon J Boulton, Junjie Chen, Dik C van Gent, Jiri Bartek, Jos Jonkers, Piet Borst, Sven Rottenberg
Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway. In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases...
May 28, 2015: Nature
Vera Boersma, Nathalie Moatti, Sandra Segura-Bayona, Marieke H Peuscher, Jaco van der Torre, Brigitte A Wevers, Alexandre Orthwein, Daniel Durocher, Jacqueline J L Jacobs
Appropriate repair of DNA lesions and the inhibition of DNA repair activities at telomeres are crucial to prevent genomic instability. By fuelling the generation of genetic alterations and by compromising cell viability, genomic instability is a driving force in cancer and ageing. Here we identify MAD2L2 (also known as MAD2B or REV7) through functional genetic screening as a novel factor controlling DNA repair activities at mammalian telomeres. We show that MAD2L2 accumulates at uncapped telomeres and promotes non-homologous end-joining (NHEJ)-mediated fusion of deprotected chromosome ends and genomic instability...
May 28, 2015: Nature
Junya Tomida, Kei-ichi Takata, Sabine S Lange, Andria C Schibler, Matthew J Yousefzadeh, Sarita Bhetawal, Sharon Y R Dent, Richard D Wood
DNA polymerase zeta (pol ζ) is exceptionally important for controlling mutagenesis and genetic instability. REV3L comprises the catalytic subunit, while REV7 (MAD2L2) is considered an accessory subunit. However, it has not been established that the role of REV7 in DNA damage tolerance is necessarily connected with mammalian pol ζ, and there is accumulating evidence that REV7 and REV3L have independent functions. Analysis of pol ζ has been hampered by difficulties in expression of REV3L in mammalian cells, and lack of a functional complementation system...
January 2015: Nucleic Acids Research
Kaoru Niimi, Yoshiki Murakumo, Naoki Watanabe, Takuya Kato, Shinji Mii, Atsushi Enomoto, Masato Asai, Naoya Asai, Eiko Yamamoto, Hiroaki Kajiyama, Kiyosumi Shibata, Fumitaka Kikkawa, Masahide Takahashi
Human REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene transcription, and carcinogenesis. In this study, we evaluated the expression of REV7 in epithelial ovarian cancer (EOC) and analyzed the association between its expression and chemosensitivity in ovarian clear cell carcinoma (CCC) cells. Expression of REV7 in human EOC tissues was assessed by immunohistochemical staining. Expression was detected in the majority of EOCs (92.0%) with especially high levels of expression frequently observed in CCCs (73...
May 2014: Cancer Science
Maryam Khalaj, Abdolrahim Abbasi, Hiroshi Yamanishi, Kouyou Akiyama, Shuso Wakitani, Sotaro Kikuchi, Michiko Hirose, Misako Yuzuriha, Masaki Magari, Heba A Degheidy, Kuniya Abe, Atsuo Ogura, Hiroshi Hashimoto, Tetsuo Kunieda
Repro22 is a mutant mouse produced via N-ethyl-N-nitrosourea-induced mutagenesis that shows sterility with germ cell depletion caused by defective proliferation of primordial germ cells, decreased body weight, and partial lethality during embryonic development. Using a positional cloning strategy, we identified a missense mutation in Rev7/Mad2l2 (Rev7(C70R)) and confirmed that the mutation is the cause of the defects in repro22 mice through transgenic rescue with normal Rev7. Rev7/Mad2l2 encodes a subunit of DNA polymerase ζ (Polζ), 1 of 10 translesion DNA synthesis polymerases known in mammals...
February 7, 2014: Journal of Biological Chemistry
Tamar Listovsky, Julian E Sale
The switch from activation of the anaphase-promoting complex/cyclosome (APC/C) by CDC20 to CDH1 during anaphase is crucial for accurate mitosis. APC/C(CDC20) ubiquitinates a limited set of substrates for subsequent degradation, including Cyclin B1 and Securin, whereas APC/C(CDH1) has a broader specificity. This switch depends on dephosphorylation of CDH1 and the APC/C, and on the degradation of CDC20. Here we show, in human cells, that the APC/C inhibitor MAD2L2 also contributes to ensuring the sequential activation of the APC/C by CDC20 and CDH1...
October 14, 2013: Journal of Cell Biology
Kozo Tanaka
No abstract text is available yet for this article.
August 2013: Seikagaku. the Journal of Japanese Biochemical Society
Mehdi Pirouz, Sven Pilarski, Michael Kessel
The development of primordial germ cells (PGCs) involves several waves of epigenetic reprogramming. A major step is following specification and involves the transition from the stably suppressive histone modification H3K9me2 to the more flexible, still repressive H3K27me3, while PGCs are arrested in G2 phase of their cycle. The significance and underlying molecular mechanism of this transition were so far unknown. Here, we generated mutant mice for the Mad2l2 (Mad2B, Rev7) gene product, and found that they are infertile in both males and females...
August 2013: PLoS Genetics
Naoki Watanabe, Shinji Mii, Naoya Asai, Masato Asai, Kaoru Niimi, Kaori Ushida, Takuya Kato, Atsushi Enomoto, Hideshi Ishii, Masahide Takahashi, Yoshiki Murakumo
REV7 (also known as MAD2L2 and MAD2B) is involved in DNA repair, cell cycle regulation, gene expression, and carcinogenesis. In vitro studies show that REV7 interacts with several proteins and regulates their function. It has been reported that human REV7 is highly expressed in the adult testis by Northern blot analysis. However, the significance of REV7 in mammalian development has not been elucidated. Here, we present analyses of REV7-deficient (Rev7(-/-)) mice to clarify the significance of Rev7 in mouse development...
April 12, 2013: Journal of Biological Chemistry
Glenda Nicioli da Silva, Elaine Aparecida de Camargo, Daisy Maria Favero Salvadori
Because of its lower toxicity and good tolerability and response, gemcitabine has been described as one of the most highly promising drugs for urinary bladder cancer therapy. Its phosphorylated active-dFdCTP metabolite can incorporate into DNA, causing replication blockage. Additionally, it is known that mutations in the TP53 gene are related to the high recurrence rate of these neoplasias. Based on these premises, we investigated the effects of gemcitabine on the expression of the cell cycle-related genes in two different TP53-mutated bladder transitional carcinoma cell lines-5637 (from a moderate-grade tumor with a TP53 allele carrying two mutations) and T24 (from an invasive tumor with a TP53 allele encoding an in-frame deletion)...
December 2012: Molecular Biology Reports
Verena Varadi, Melanie Bevier, Ewa Grzybowska, Robert Johansson, Kerstin Enquist, Roger Henriksson, Dorota Butkiewicz, Jolanta Pamula-Pilat, Karolina Tecza, Kari Hemminki, Per Lenner, Asta Försti
Chromosomal instability is a known hallmark of many cancers. DNA polymerases represent a group of enzymes that are involved in the mechanism of chromosomal instability as they have a central function in DNA metabolism. We hypothesized that genetic variation in the polymerase genes may affect gene expression or protein configuration and by that cancer risk and clinical outcome. We selected four genes encoding for the catalytic subunits of the polymerases β, δ, θ and ζ (POLB, POLD1, POLQ and REV3L, respectively) and two associated proteins (MAD2L2 and REV1) because of their previously reported association with chromosomal instability and/or tumorigenesis...
August 2011: Breast Cancer Research and Treatment
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