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https://www.readbyqxmd.com/read/29768208/the-cst-complex-mediates-end-protection-at-double-strand-breaks-and-promotes-parp-inhibitor-sensitivity-in-brca1-deficient-cells
#1
Marco Barazas, Stefano Annunziato, Stephen J Pettitt, Inge de Krijger, Hind Ghezraoui, Stefan J Roobol, Catrin Lutz, Jessica Frankum, Fei Fei Song, Rachel Brough, Bastiaan Evers, Ewa Gogola, Jinhyuk Bhin, Marieke van de Ven, Dik C van Gent, Jacqueline J L Jacobs, Ross Chapman, Christopher J Lord, Jos Jonkers, Sven Rottenberg
Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration of BRCA1-independent homologous recombination through loss of factors such as 53BP1, RIF1, and REV7/MAD2L2, which inhibit end resection of DNA double-strand breaks (DSBs). To identify additional factors involved in this process, we performed CRISPR/SpCas9-based loss-of-function screens and selected for factors that confer PARP inhibitor (PARPi) resistance in BRCA1-deficient cells...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29748565/genome-wide-and-high-density-crispr-cas9-screens-identify-point-mutations-in-parp1-causing-parp-inhibitor-resistance
#2
Stephen J Pettitt, Dragomir B Krastev, Inger Brandsma, Amy Dréan, Feifei Song, Radoslav Aleksandrov, Maria I Harrell, Malini Menon, Rachel Brough, James Campbell, Jessica Frankum, Michael Ranes, Helen N Pemberton, Rumana Rafiq, Kerry Fenwick, Amanda Swain, Sebastian Guettler, Jung-Min Lee, Elizabeth M Swisher, Stoyno Stoynov, Kosuke Yusa, Alan Ashworth, Christopher J Lord
Although PARP inhibitors (PARPi) target homologous recombination defective tumours, drug resistance frequently emerges, often via poorly understood mechanisms. Here, using genome-wide and high-density CRISPR-Cas9 "tag-mutate-enrich" mutagenesis screens, we identify close to full-length mutant forms of PARP1 that cause in vitro and in vivo PARPi resistance. Mutations both within and outside of the PARP1 DNA-binding zinc-finger domains cause PARPi resistance and alter PARP1 trapping, as does a PARP1 mutation found in a clinical case of PARPi resistance...
May 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29697047/rev7-and-53bp1-crb2-prevent-recq-helicase-dependent-hyper-resection-of-dna-double-strand-breaks
#3
Bryan A Leland, Angela C Chen, Amy Y Zhao, Robert C Wharton, Megan C King
Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of either 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2...
April 26, 2018: ELife
https://www.readbyqxmd.com/read/29454027/selection-of-biomarkers-for-hiv-1-latency-by-integrated-analysis
#4
Sun Young Lee, Byeong-Sun Choi, Cheol-Hee Yoon, Chun Kang, Kisoon Kim, Kyung-Chang Kim
A major obstacle in the treatment of human immunodeficiency virus type 1 (HIV-1) is its ability to establish latent infection. To find novel biomarkers associated with the mechanism of HIV-1 latent infection, we identified 70 candidate genes in HIV-1 latently infected cells through the integrated analysis in a previous study. It is important to select more effective biomarkers among 70 candidates and to verify the possibility of selected biomarkers for HIV-1 latency. We identified the 24 and 25 genes from 70 candidate genes in significantly enriched categories selected by Database for Annotation, Visualization and Integrated Discovery (DAVID) software and Gene Set Enrichment Analysis (GSEA) software, respectively...
February 14, 2018: Genomics
https://www.readbyqxmd.com/read/29360267/mad2l2-inhibits-colorectal-cancer-growth-by-promoting-ncoa3-ubiquitination-and-degradation
#5
Yixin Li, Liren Li, Miao Chen, Xinfa Yu, Zhuoyu Gu, Huijuan Qiu, Ge Qin, Qian Long, Xiaoyan Fu, Tianze Liu, Wenbin Li, Wenlin Huang, Dingbo Shi, Tiebang Kang, Meihua Luo, Xiaojun Wu, Wuguo Deng
Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation (IP) coupled with mass spectrometry (IP-MS) analysis was used to detect, identify, and verify the proteins that interacted with NCOA3 in CRC cells...
March 2018: Molecular Oncology
https://www.readbyqxmd.com/read/29203878/atm-and-cdk2-control-chromatin-remodeler-csb-to-inhibit-rif1-in-dsb-repair-pathway-choice
#6
Nicole L Batenburg, John R Walker, Sylvie M Noordermeer, Nathalie Moatti, Daniel Durocher, Xu-Dong Zhu
CSB, a member of the SWI2/SNF2 superfamily, is implicated in DNA double-strand break (DSB) repair. However, how it regulates this repair process is poorly understood. Here we uncover that CSB interacts via its newly identified winged helix domain with RIF1, an effector of 53BP1, and that this interaction mediates CSB recruitment to DSBs in S phase. At DSBs, CSB remodels chromatin by evicting histones, which limits RIF1 and its effector MAD2L2 but promotes BRCA1 accumulation. The chromatin remodeling activity of CSB requires not only damage-induced phosphorylation on S10 by ATM but also cell cycle-dependent phosphorylation on S158 by cyclin A-CDK2...
December 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/29160738/h4k20me2-distinguishes-pre-replicative-from-post-replicative-chromatin-to-appropriately-direct-dna-repair-pathway-choice-by-53bp1-rif1-mad2l2
#7
Marco Simonetta, Inge de Krijger, Judit Serrat, Nathalie Moatti, Diogo Fortunato, Liesbeth Hoekman, Onno B Bleijerveld, A F Maarten Altelaar, Jacqueline J L Jacobs
The main pathways for the repair of DNA double strand breaks (DSBs) are non-homologous end-joining (NHEJ) and homologous recombination directed repair (HDR). These operate mutually exclusive and are activated by 53BP1 and BRCA1, respectively. As HDR can only succeed in the presence of an intact copy of replicated DNA, cells employ several mechanisms to inactivate HDR in the G1 phase of cell cycle. As cells enter S-phase, these inhibitory mechanisms are released and HDR becomes active. However, during DNA replication, NHEJ and HDR pathways are both functional and non-replicated and replicated DNA regions co-exist, with the risk of aberrant HDR activity at DSBs in non-replicated DNA...
2018: Cell Cycle
https://www.readbyqxmd.com/read/28887307/dynamic-feature-of-mitotic-arrest-deficient-2-like-protein-2-mad2l2-and-structural-basis-for-its-interaction-with-chromosome-alignment-maintaining-phosphoprotein-camp
#8
Kodai Hara, Shota Taharazako, Masanori Ikeda, Hiroki Fujita, Yoshiko Mikami, Sotaro Kikuchi, Asami Hishiki, Hideshi Yokoyama, Yoshinobu Ishikawa, Shin-Ichiro Kanno, Kozo Tanaka, Hiroshi Hashimoto
Mitotic arrest deficient 2-like protein 2 (MAD2L2), also termed MAD2B or REV7, is involved in multiple cellular functions including translesion DNA synthesis (TLS), signal transduction, transcription, and mitotic events. MAD2L2 interacts with chromosome alignment-maintaining phosphoprotein (CAMP), a kinetochore-microtubule attachment protein in mitotic cells, presumably through a novel "WK" motif in CAMP. Structures of MAD2L2 in complex with binding regions of the TLS proteins REV3 and REV1 have revealed that MAD2L2 has two faces for protein-protein interactions that are regulated by its C-terminal region; however, the mechanisms underlying the MAD2L2-CAMP interaction and the mitotic role of MAD2L2 remain unknown...
October 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28881617/germline-whole-exome-sequencing-and-large-scale-replication-identifies-fancm-as-a-likely-high-grade-serous-ovarian-cancer-susceptibility-gene
#9
Ed Dicks, Honglin Song, Susan J Ramus, Elke Van Oudenhove, Jonathan P Tyrer, Maria P Intermaggio, Siddhartha Kar, Patricia Harrington, David D Bowtell, Aocs Study Group, Mine S Cicek, Julie M Cunningham, Brooke L Fridley, Jennifer Alsop, Mercedes Jimenez-Linan, Anna Piskorz, Teodora Goranova, Emma Kent, Nadeem Siddiqui, James Paul, Robin Crawford, Samantha Poblete, Shashi Lele, Lara Sucheston-Campbell, Kirsten B Moysich, Weiva Sieh, Valerie McGuire, Jenny Lester, Kunle Odunsi, Alice S Whittemore, Natalia Bogdanova, Matthias Dürst, Peter Hillemanns, Beth Y Karlan, Aleksandra Gentry-Maharaj, Usha Menon, Marc Tischkowitz, Douglas Levine, James D Brenton, Thilo Dörk, Ellen L Goode, Simon A Gayther, D P Paul Pharoah
We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10(-3)). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28440919/rev7-the-regulatory-subunit-of-pol%C3%AE-undergoes-uv-induced-and-cul4-dependent-degradation
#10
Audesh Bhat, Zhoushuai Qin, Guifen Wang, Wangyang Chen, Wei Xiao
In eukaryotic cells, Rev7 interacts with Rev3 and functions as a regulatory subunit of Polζ, a translesion DNA synthesis (TLS) polymerase. In addition to its role in TLS, mammalian Rev7, also known as Mad2B/Mad2L2, participates in multiple cellular activities including cell cycle progression and double-strand break repair through its interaction with several proteins. Here we show that in mammalian cells, Rev7 undergoes ubiquitin/proteasome-mediated degradation upon UV irradiation in a time-dependent manner...
June 2017: FEBS Journal
https://www.readbyqxmd.com/read/28404948/germline-whole-exome-sequencing-and-large-scale-replication-identifies-fancm-as-a-likely-high-grade-serous-ovarian-cancer-susceptibility-gene
#11
Ed Dicks, Honglin Song, Susan J Ramus, Elke Van Oudenhove, Jonathan P Tyrer, Maria P Intermaggio, Siddhartha Kar, Patricia Harrington, David D Bowtell, Aocs Study Group, Mine S Cicek, Julie M Cunningham, Brooke L Fridley, Jennifer Alsop, Mercedes Jimenez-Linan, Anna Piskorz, Teodora Goranova, Emma Kent, Nadeem Siddiqui, James Paul, Robin Crawford, Samantha Poblete, Shashi Lele, Lara Sucheston-Campbell, Kirsten B Moysich, Weiva Sieh, Valerie McGuire, Jenny Lester, Kunle Odunsi, Alice S Whittemore, Natalia Bogdanova, Matthias Dürst, Peter Hillemanns, Beth Y Karlan, Aleksandra Gentry-Maharaj, Usha Menon, Marc Tischkowitz, Douglas Levine, James D Brenton, Thilo Dörk, Ellen L Goode, Simon A Gayther, Paul D P Pharoah
We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8x10-3). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28330620/mad2l2-promotes-open-chromatin-in-embryonic-stem-cells-and-derepresses-the-dppa3-locus
#12
Ali Rahjouei, Mehdi Pirouz, Michela Di Virgilio, Dirk Kamin, Michael Kessel
The chromatin of naive embryonic stem cells (ESCs) has a largely open configuration, as evident by the lack of condensed heterochromatin and the hypomethylation of DNA. Several molecular mechanisms promoting this constellation were previously identified. Here we present evidence for an important epigenetic function of MAD2L2, a protein originally known for its role in DNA damage repair, and for its requirement in germ cell development. We demonstrate using super-resolution microscopy that numerous MAD2L2 microfoci are exclusively associated with euchromatin, similar to other factors of the DNA damage response...
April 11, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/27816361/genetic-variants-in-cd44-and-mat1a-confer-susceptibility-to-acute-skin-reaction-in-breast-cancer-patients-undergoing-radiation-therapy
#13
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
https://www.readbyqxmd.com/read/27712588/knockdown-of-rev7-inhibits-breast-cancer-cell-migration-and-invasion
#14
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
https://www.readbyqxmd.com/read/27500492/biallelic-inactivation-of-rev7-is-associated-with-fanconi-anemia
#15
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
https://www.readbyqxmd.com/read/26697843/rev7-mad2b-plays-a-critical-role-in-the-assembly-of-a-functional-mitotic-spindle
#16
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
https://www.readbyqxmd.com/read/26474871/visceral-obesity-stimulates-anaphase-bridge-formation-and-spindle-assembly-checkpoint-dysregulation-in-radioresistant-oesophageal-adenocarcinoma
#17
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
https://www.readbyqxmd.com/read/26152289/association-between-cell-cycle-gene-transcription-and-tumor-size-in-oral-squamous-cell-carcinoma
#18
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
https://www.readbyqxmd.com/read/25928475/destabilization-of-pluripotency-in-the-absence-of-mad2l2
#19
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
https://www.readbyqxmd.com/read/25896508/rev7-mad2l2-the-multitasking-maestro-emerges-as-a-barrier-to-recombination
#20
COMMENT
Julian E Sale
No abstract text is available yet for this article.
June 12, 2015: EMBO Journal
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