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https://www.readbyqxmd.com/read/28369583/substrate-preference-of-gen-endonucleases-highlights-the-importance-of-branched-structures-as-dna-damage-repair-intermediates
#1
Stephanie P Bellendir, Danielle J Rognstad, Lydia P Morris, Grzegorz Zapotoczny, William G Walton, Matthew R Redinbo, Dale A Ramsden, Jeff Sekelsky, Dorothy A Erie
Human GEN1 and yeast Yen1 are endonucleases with the ability to cleave Holliday junctions (HJs), which are proposed intermediates in recombination. In vivo, GEN1 and Yen1 function secondarily to Mus81, which has weak activity on intact HJs. We show that the genetic relationship is reversed in Drosophila, with Gen mutants having more severe defects than mus81 mutants. In vitro, DmGen, like HsGEN1, efficiently cleaves HJs, 5΄ flaps, splayed arms, and replication fork structures. We find that the cleavage rates for 5΄ flaps are significantly higher than those for HJs for both DmGen and HsGEN1, even in vast excess of enzyme over substrate...
May 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28357386/a-new-role-for-holliday-junction-resolvase-yen1-in-processing-dna-replication-intermediates-exposes-dna2-as-an-accessory-replicative-helicase
#2
COMMENT
Benoît Falquet, Ulrich Rass
DNA replication is mediated by a multi-protein complex known as the replisome. With the hexameric MCM (minichromosome maintenance) replicative helicase at its core, the replisome splits the parental DNA strands, forming replication forks (RFs), where it catalyses coupled leading and lagging strand DNA synthesis. While replication is a highly effective process, intrinsic and oncogene-induced replication stress impedes the progression of replisomes along chromosomes. As a consequence, RFs stall, arrest, and collapse, jeopardizing genome stability...
January 2, 2017: Microbial Cell
https://www.readbyqxmd.com/read/28346343/lifetime-exposure-to-a-constant-environment-amplifies-the-impact-of-a-fructose-rich-diet-on-glucose-homeostasis-during-pregnancy
#3
Aleida Song, Stuart Astbury, Abha Hoedl, Brent Nielsen, Michael E Symonds, Rhonda C Bell
The need to refine rodent models of human-related disease is now being recognized, in particular the rearing environment that can profoundly modulate metabolic regulation. Most studies on pregnancy and fetal development purchase and transport young females into the research facility, which after a short period of acclimation are investigated (Gen0). We demonstrate that female offspring (Gen1) show an exaggerated hyperinsulinemic response to pregnancy when fed a standard diet and with high fructose intake, which continues throughout pregnancy...
March 25, 2017: Nutrients
https://www.readbyqxmd.com/read/28327556/control-of-structure-specific-endonucleases-to-maintain-genome-stability
#4
REVIEW
Pierre-Marie Dehé, Pierre-Henri L Gaillard
Structure-specific endonucleases (SSEs) have key roles in DNA replication, recombination and repair, and emerging roles in transcription. These enzymes have specificity for DNA secondary structure rather than for sequence, and therefore their activity must be precisely controlled to ensure genome stability. In this Review, we discuss how SSEs are controlled as part of genome maintenance pathways in eukaryotes, with an emphasis on the elaborate mechanisms that regulate the members of the major SSE families - including the xeroderma pigmentosum group F-complementing protein (XPF) and MMS and UV-sensitive protein 81 (MUS81)-dependent nucleases, and the flap endonuclease 1 (FEN1), XPG and XPG-like endonuclease 1 (GEN1) enzymes - during processes such as DNA adduct repair, Holliday junction processing and replication stress...
May 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28290553/slx4-prevents-gen1-dependent-dsbs-during-dna-replication-arrest-under-pathological-conditions-in-human-cells
#5
Eva Malacaria, Annapaola Franchitto, Pietro Pichierri
SLX4 is a versatile protein serving as docking for multiple structure-specific endonucleases during DNA repair, however, little is known about its function at demised replication forks. Using RNAi or FA-P cells complemented with SLX4 mutants that abrogate interaction with MUS81 or SLX1, we show that SLX4 cooperates with MUS81 to introduce DSBs after replication stress but also counteracts pathological targeting of demised forks by GEN1. Such unexpected function of SLX4 is unrelated to interaction with endonucleases, but concerns the physical presence of the protein...
March 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28090586/holliday-junction-trap-shows-how-cells-use-recombination-and-a-junction-guardian-role-of-recq-helicase
#6
Jun Xia, Li-Tzu Chen, Qian Mei, Chien-Hui Ma, Jennifer A Halliday, Hsin-Yu Lin, David Magnan, John P Pribis, Devon M Fitzgerald, Holly M Hamilton, Megan Richters, Ralf B Nehring, Xi Shen, Lei Li, David Bates, P J Hastings, Christophe Herman, Makkuni Jayaram, Susan M Rosenberg
DNA repair by homologous recombination (HR) underpins cell survival and fuels genome instability, cancer, and evolution. However, the main kinds and sources of DNA damage repaired by HR in somatic cells and the roles of important HR proteins remain elusive. We present engineered proteins that trap, map, and quantify Holliday junctions (HJs), a central DNA intermediate in HR, based on catalytically deficient mutant RuvC protein of Escherichia coli. We use RuvCDefGFP (RDG) to map genomic footprints of HR at defined DNA breaks in E...
November 2016: Science Advances
https://www.readbyqxmd.com/read/28049850/resolution-of-single-and-double-holliday-junction-recombination-intermediates-by-gen1
#7
Rajvee Shah Punatar, Maria Jose Martin, Haley D M Wyatt, Ying Wai Chan, Stephen C West
Genetic recombination provides an important mechanism for the repair of DNA double-strand breaks. Homologous pairing and strand exchange lead to the formation of DNA intermediates, in which sister chromatids or homologous chromosomes are covalently linked by four-way Holliday junctions (HJs). Depending on the type of recombination reaction that takes place, intermediates may have single or double HJs, and their resolution is essential for proper chromosome segregation. In mitotic cells, double HJs are primarily dissolved by the BLM helicase-TopoisomeraseIIIα-RMI1-RMI2 (BTR) complex, whereas single HJs (and double HJs that have escaped the attention of BTR) are resolved by structure-selective endonucleases known as HJ resolvases...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28049740/resolvase-osgen1-mediates-dna-repair-by-homologous-recombination
#8
Chong Wang, James D Higgins, Yi He, Pingli Lu, Dabing Zhang, Wanqi Liang
Yen1/GEN1 are canonical Holliday junction resolvases that belong to the RAD2/XPG family. In eukaryotes, such as budding yeast, mice, worms, and humans, Yen1/GEN1 work together with Mus81-Mms4/MUS81-EME1 and Slx1-Slx4/SLX1-SLX4 in DNA repair by homologous recombination to maintain genome stability. In plants, the biological function of Yen1/GEN1 remains largely unclear. In this study, we characterized the loss of function mutants of OsGEN1 and OsSEND1, a pair of paralogs of Yen1/GEN1 in rice (Oryza sativa). We first investigated the role of OsGEN1 during meiosis and found a reduction in chiasma frequency by ∼6% in osgen1 mutants, compared to the wild type, suggesting a possible involvement of OsGEN1 in the formation of crossovers...
February 2017: Plant Physiology
https://www.readbyqxmd.com/read/27990631/holliday-junction-resolving-enzymes-structures-and-mechanisms
#9
REVIEW
David M J Lilley
Holliday junction-resolving enzymes are nucleases that are highly specific for the structure of the junction, to which they bind in dimeric form. Two symmetrically disposed cleavages are made. These are not simultaneous, but the second cleavage is accelerated relative to the first, so ensuring that bilateral cleavage occurs during the lifetime of the DNA-protein complex. In eukaryotic cells there are two known junction-resolving activities. GEN1 is similar to enzymes from lower organisms. A crystallographic structure of a fungal GEN1 bound to the product of resolution has been determined...
April 2017: FEBS Letters
https://www.readbyqxmd.com/read/27383418/gen1-and-eme1-play-redundant-roles-in-dna-repair-and-meiotic-recombination-in-mice
#10
Xiaowen Wang, Herui Wang, Bin Guo, Ya Zhang, Yinv Gong, Chi Zhang, Hong Xu, Xiaohui Wu
Resolution of the Holliday junction (HJ) is essential for homologous recombination and DNA repair. In Saccharomyces cerevisiae, HJ resolvase Yen1 and the Mus81-Mms4 complex are redundant in DNA damage repair. In cultured mammalian cells, such redundancy also exists between Yen1 ortholog GEN1 and the Mus81-Mms1 ortholog MUS81-EME1. In this report, we further tested if GEN1 and EME1 redundantly affect HJ-related physiological processes in mice. We found that combined homozygous mutations of Gen1 and Eme1 led to synthetic lethality during early embryonic stages...
October 2016: DNA and Cell Biology
https://www.readbyqxmd.com/read/27284361/effect-of-gen1-interference-on-the-chemosensitivity-of-the-breast-cancer-mcf-7-and-skbr3-cell-lines
#11
Yunlu Wu, Ying Qian, Guozhong Zhou, Juan Lv, Qiuyue Yan, Xuejun Dong
Chemotherapy is a notable method for the treatment of breast cancer. Numerous genes associated with the sensitivity of cancer to chemotherapy have been found. In recent years, evidence has suggested that a particular structure termed Holliday junction (HJ) plays a crucial role in cancer chemosensitivity. Targeting HJ resolvases, such as structure-specific endonuclease subunit SLX4 (Slx4) and MUS81 structure-specific endonuclease subunit (Mus81), significantly increases the chemosensitivity of tumor cells. Flap endonuclease GEN homolog 1 (GEN1) is a HJ resolvase that belongs to the Rad2/xeroderma pigmentosum complementation group G nuclease family...
June 2016: Oncology Letters
https://www.readbyqxmd.com/read/26970388/cell-cycle-control-of-dna-joint-molecule-resolution
#12
REVIEW
Philipp Wild, Joao Matos
The establishment of stable interactions between chromosomes underpins vital cellular processes such as recombinational DNA repair and bipolar chromosome segregation. On the other hand, timely disengagement of persistent connections is necessary to assure efficient partitioning of the replicated genome prior to cell division. Whereas great progress has been made in defining how cohesin-mediated chromosomal interactions are disengaged as cells prepare to undergo chromosome segregation, little is known about the metabolism of DNA joint molecules (JMs), generated during the repair of chromosomal lesions...
June 2016: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/26970083/a-high-rate-of-telomeric-sister-chromatid-exchange-occurs-in-chronic-lymphocytic-leukaemia-b-cells
#13
Sandrine Medves, Morgan Auchter, Laetitia Chambeau, Sophie Gazzo, Delphine Poncet, Blandine Grangier, Aurélie Verney, Etienne Moussay, Wim Ammerlaan, Gabriel Brisou, Hamid Morjani, Vincent Géli, Valérie Palissot, Guy Berchem, Gilles Salles, Thomas Wenner
Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e...
July 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/26947968/cystatin-c-standardization-decreases-assay-variation-and-improves-assessment-of-glomerular-filtration-rate
#14
Natalie Ebert, Pierre Delanaye, Michael Shlipak, Olga Jakob, Peter Martus, Jan Bartel, Jens Gaedeke, Markus van der Giet, Mirjam Schuchardt, Etienne Cavalier, Elke Schaeffner
BACKGROUND: Cystatin C is increasingly used in glomerular filtration rate (GFR) estimation equations. The dependence of cystatin C results upon the analytical method has been a major source of controversy. METHODS: Cystatin C was measured with non-standardized turbidimetric Roche Generation 1 and standardized nephelometric Siemens assays in 3666 and additionally with standardized Roche Generation 2 and Siemens in 567 blood samples of the Berlin Initiative Study...
May 1, 2016: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/26686639/crystal-structure-of-a-eukaryotic-gen1-resolving-enzyme-bound-to-dna
#15
Yijin Liu, Alasdair D J Freeman, Anne-Cécile Déclais, Timothy J Wilson, Anton Gartner, David M J Lilley
We present the crystal structure of the junction-resolving enzyme GEN1 bound to DNA at 2.5 Å resolution. The structure of the GEN1 protein reveals it to have an elaborated FEN-XPG family fold that is modified for its role in four-way junction resolution. The functional unit in the crystal is a monomer of active GEN1 bound to the product of resolution cleavage, with an extensive DNA binding interface for both helical arms. Within the crystal lattice, a GEN1 dimer interface juxtaposes two products, whereby they can be reconnected into a four-way junction, the structure of which agrees with that determined in solution...
December 22, 2015: Cell Reports
https://www.readbyqxmd.com/read/26682650/human-holliday-junction-resolvase-gen1-uses-a-chromodomain-for-efficient-dna-recognition-and-cleavage
#16
Shun-Hsiao Lee, Lissa Nicola Princz, Maren Felizitas Klügel, Bianca Habermann, Boris Pfander, Christian Biertümpfel
Holliday junctions (HJs) are key DNA intermediates in homologous recombination. They link homologous DNA strands and have to be faithfully removed for proper DNA segregation and genome integrity. Here, we present the crystal structure of human HJ resolvase GEN1 complexed with DNA at 3.0 Å resolution. The GEN1 core is similar to other Rad2/XPG nucleases. However, unlike other members of the superfamily, GEN1 contains a chromodomain as an additional DNA interaction site. Chromodomains are known for their chromatin-targeting function in chromatin remodelers and histone(de)acetylases but they have not previously been found in nucleases...
December 18, 2015: ELife
https://www.readbyqxmd.com/read/26370409/resolution-of-recombination-intermediates-mechanisms-and-regulation
#17
REVIEW
Stephen C West, Miguel G Blanco, Ying Wai Chan, Joao Matos, Shriparna Sarbajna, Haley D M Wyatt
DNA strand break repair by homologous recombination leads to the formation of intermediates in which sister chromatids are covalently linked. The efficient processing of these joint molecules, which often contain four-way structures known as Holliday junctions, is necessary for efficient chromosome segregation during mitotic division. Because persistent chromosome bridges pose a threat to genome stability, cells ensure the complete elimination of joint molecules through three independent pathways. These involve (1) BLM-Topoisomerase IIIα-RMI1-RMI2 (BTR complex), (2) SLX1-SLX4-MUS81-EME1 (SLX-MUS complex), and (3) GEN1...
2015: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/26301691/hemagglutinin-stem-nanoparticles-generate-heterosubtypic-influenza-protection
#18
Hadi M Yassine, Jeffrey C Boyington, Patrick M McTamney, Chih-Jen Wei, Masaru Kanekiyo, Wing-Pui Kong, John R Gallagher, Lingshu Wang, Yi Zhang, M Gordon Joyce, Daniel Lingwood, Syed M Moin, Hanne Andersen, Yoshinobu Okuno, Srinivas S Rao, Audray K Harris, Peter D Kwong, John R Mascola, Gary J Nabel, Barney S Graham
The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain...
September 2015: Nature Medicine
https://www.readbyqxmd.com/read/26284109/hold-your-horsses-controlling-structure-selective-endonucleases-mus81-and-yen1-gen1
#19
REVIEW
Miguel G Blanco, Joao Matos
Repair of DNA lesions through homologous recombination promotes the establishment of stable chromosomal interactions. Multiple helicases, topoisomerases and structure-selective endonucleases (SSEs) act upon recombining joint molecules (JMs) to disengage chromosomal connections and safeguard chromosome segregation. Recent studies on two conserved SSEs - MUS81 and Yen1/GEN1- uncovered multiple layers of regulation that operate to carefully tailor JM-processing according to specific cellular needs. Temporal restriction of SSE function imposes a hierarchy in pathway usage that ensures efficient JM-processing while minimizing reciprocal exchanges between the recombining DNAs...
2015: Frontiers in Genetics
https://www.readbyqxmd.com/read/26201965/whole-exome-sequencing-of-a-rare-case-of-familial-childhood-acute-lymphoblastic-leukemia-reveals-putative-predisposing-mutations-in-fanconi-anemia-genes
#20
Jean-François Spinella, Jasmine Healy, Virginie Saillour, Chantal Richer, Pauline Cassart, Manon Ouimet, Daniel Sinnett
BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. While the multi-step model of pediatric leukemogenesis suggests interplay between constitutional and somatic genomes, the role of inherited genetic variability remains largely undescribed. Nonsyndromic familial ALL, although extremely rare, provides the ideal setting to study inherited contributions to ALL. Toward this goal, we sequenced the exomes of a childhood ALL family consisting of mother, father and two non-twinned siblings diagnosed with concordant pre-B hyperdiploid ALL and previously shown to have inherited a rare form of PRDM9, a histone H3 methyltransferase involved in crossing-over at recombination hotspots and Holliday junctions...
2015: BMC Cancer
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