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https://www.readbyqxmd.com/read/27383418/gen1-and-eme1-play-redundant-roles-in-dna-repair-and-meiotic-recombination-in-mice
#1
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...
July 6, 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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/25483196/the-basic-n-terminal-domain-of-trf2-limits-recombination-endonuclease-action-at-human-telomeres
#12
Adélaïde Saint-Léger, Melanie Koelblen, Livia Civitelli, Amadou Bah, Nadir Djerbi, Marie-Josèphe Giraud-Panis, Arturo Londoño-Vallejo, Fiorentina Ascenzioni, Eric Gilson
The stability of mammalian telomeres depends upon TRF2, which prevents inappropriate repair and checkpoint activation. By using a plasmid integration assay in yeasts carrying humanized telomeres, we demonstrated that TRF2 possesses the intrinsic property to both stimulate initial homologous recombination events and to prevent their resolution via its basic N-terminal domain. In human cells, we further showed that this TRF2 domain prevents telomere shortening mediated by the resolvase-associated protein SLX4 as well as GEN1 and MUS81, 2 different types of endonucleases with resolvase activities...
2014: Cell Cycle
https://www.readbyqxmd.com/read/25466415/mus81-mms4-and-yen1-resolve-a-novel-anaphase-bridge-formed-by-noncanonical-holliday-junctions
#13
Jonay García-Luis, Félix Machín
Downregulation of separase, condensin, Smc5/6, topoisomerase II and Cdc14 in Saccharomyces cerevisiae yields anaphase bridges formed by unresolved sister chromatids (SCBs). Here we report that the overlapping actions of the structure-selective endonucleases (SSEs) Mus81-Mms4/EME1 and Yen1/GEN1, but not Slx1-Slx4, are also essential to prevent the formation of spontaneous SCBs that depend on the homologous recombination pathway. We further show that the frequency of SCBs is boosted after mild replication stress and that they contain joint molecules enriched in non-canonical forms of the Holliday junction (HJ), including nicked-HJ (nHJ)...
2014: Nature Communications
https://www.readbyqxmd.com/read/25315822/gen1-from-a-thermophilic-fungus-is-functionally-closely-similar-to-non-eukaryotic-junction-resolving-enzymes
#14
Alasdair D J Freeman, Yijin Liu, Anne-Cécile Déclais, Anton Gartner, David M J Lilley
Processing of Holliday junctions is essential in recombination. We have identified the gene for the junction-resolving enzyme GEN1 from the thermophilic fungus Chaetomium thermophilum and expressed the N-terminal 487-amino-acid section. The protein is a nuclease that is highly selective for four-way DNA junctions, cleaving 1nt 3' to the point of strand exchange on two strands symmetrically disposed about a diagonal axis. CtGEN1 binds to DNA junctions as a discrete homodimer with nanomolar affinity. Analysis of the kinetics of cruciform cleavage shows that cleavage of the second strand occurs an order of magnitude faster than the first cleavage so as to generate a productive resolution event...
December 12, 2014: Journal of Molecular Biology
https://www.readbyqxmd.com/read/25209024/spatial-control-of-the-gen1-holliday-junction-resolvase-ensures-genome-stability
#15
Ying Wai Chan, Stephen C West
Holliday junction (HJ) resolvases are necessary for the processing of persistent recombination intermediates before cell division. Their actions, however, need to be restricted to the late stages of the cell cycle to avoid the inappropriate cleavage of replication intermediates. Control of the yeast HJ resolvase, Yen1, involves phosphorylation changes that modulate its catalytic activity and nuclear import. Here, we show that GEN1, the human ortholog of Yen1, is regulated by a different mechanism that is independent of phosphorylation...
September 11, 2014: Nature Communications
https://www.readbyqxmd.com/read/25131815/holliday-junction-processing-enzymes-as-guardians-of-genome-stability
#16
REVIEW
Shriparna Sarbajna, Stephen C West
Holliday junctions (HJs) are four-stranded DNA intermediates that arise during the recombinational repair of DNA double-strand breaks (DSBs). Their timely removal is crucial for faithful chromosome segregation and genome stability. In mammalian cells, HJs are processed by the BTR (BLM-topoisomerase IIIα-RMI1-RMI2) complex, the SLX-MUS (SLX1-SLX4-MUS81-EME1) complex, and the GEN1 resolvase. Recent studies have linked the deficiency of one or more of these enzymes to perturbed DNA replication, impaired crosslink repair, chromosomal instability, and defective mitoses, coupled with the transmission of widespread DNA damage and high levels of mortality...
September 2014: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/25037209/atgen1-and-atsend1-two-paralogs-in-arabidopsis-possess-holliday-junction-resolvase-activity
#17
Markus Bauknecht, Daniela Kobbe
Holliday junctions (HJs) are physical links between homologous DNA molecules that arise as central intermediary structures during homologous recombination and repair in meiotic and somatic cells. It is necessary for these structures to be resolved to ensure correct chromosome segregation and other functions. In eukaryotes, including plants, homologs of a gene called XPG-like endonuclease1 (GEN1) have been identified that process HJs in a manner analogous to the HJ resolvases of phages, archaea, and bacteria...
September 2014: Plant Physiology
https://www.readbyqxmd.com/read/24980922/expression-and-localization-of-gen1-in-mouse-mammary-epithelial-cells
#18
Lihua Sun, Yifang Zhang, Zhenxiang Pan, Bingjin Li, Mei Sun, Xingyi Zhang
GEN1, a Holliday junction resolvase, is involved in homologous repair of DNA double strand break and in maintaining centrosome integrity. Although GEN1 mutants have been reported in breast cancer patients and cell lines, little is currently known about the functions of GEN1 in the development and oncogenic transformation of mammary gland. In the present study, we demonstrate that GEN1 expression is correlated with mammary epithelial cell proliferation, differentiation in various physiological stages as well as casein...
October 2014: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/24967906/the-basic-n-terminal-domain-of-trf2-limits-recombination-endonuclease-action-at-human-telomeres
#19
Adélaïde Saint-Léger, Melanie Koelblen, Livia Civitelli, Amadou Bah, Nadir Djerbi, Marie-Josèphe Giraud-Panis, Arturo Londoño-Vallejo, Fiorentina Ascenzioni, Eric Gilson
The stability of mammalian telomeres depends upon TRF2, which prevents inappropriate repair and checkpoint activation. By using a plasmid integration assay in yeasts carrying humanized telomeres, we demonstrated that TRF2 possesses the intrinsic property to both stimulate initial homologous recombination events and to prevent their resolution via its basic N-terminal domain. In human cells, we further showed that this TRF2 domain prevents telomere shortening mediated by the resolvase-associated protein SLX4 as well as GEN1 and MUS81, 2 different types of endonucleases with resolvase activities...
June 26, 2014: Cell Cycle
https://www.readbyqxmd.com/read/24962627/detection-of-genome-wide-copy-number-variations-in-two-chicken-lines-divergently-selected-for-abdominal-fat-content
#20
Hui Zhang, Zhi-Qiang Du, Jia-Qiang Dong, Hai-Xia Wang, Hong-Yan Shi, Ning Wang, Shou-Zhi Wang, Hui Li
BACKGROUND: The chicken (Gallus gallus) is an important model organism that bridges the evolutionary gap between mammals and other vertebrates. Copy number variations (CNVs) are a form of genomic structural variation widely distributed in the genome. CNV analysis has recently gained greater attention and momentum, as the identification of CNVs can contribute to a better understanding of traits important to both humans and other animals. To detect chicken CNVs, we genotyped 475 animals derived from two broiler chicken lines divergently selected for abdominal fat content using chicken 60 K SNP array, which is a high-throughput method widely used in chicken genomics studies...
2014: BMC Genomics
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