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https://www.readbyqxmd.com/read/28049740/resolvase-osgen1-mediates-dna-repair-by-homologous-recombination
#1
Chong Wang, James Higgins, Yi He, Pingli Lu, Dabing Zhang, Wanqi Liang
Yen1/GEN1 are canonical Holliday Junction (HJ) 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. We first investigated the role of OsGEN1 during meiosis and found a reduction in chiasma frequency by ~6% in osgen1 mutants, compared to wild type, suggesting a possible involvement of OsGEN1 in the formation of crossovers...
January 3, 2017: Plant Physiology
https://www.readbyqxmd.com/read/27997828/a-mechanism-for-controlled-breakage-of-under-replicated-chromosomes-during-mitosis
#2
Heike Duda, Meret Arter, Jiradet Gloggnitzer, Federico Teloni, Philipp Wild, Miguel G Blanco, Matthias Altmeyer, Joao Matos
While DNA replication and mitosis occur in a sequential manner, precisely how cells maintain their temporal separation and order remains elusive. Here, we unveil a double-negative feedback loop between replication intermediates and an M-phase-specific structure-selective endonuclease, MUS81-SLX4, which renders DNA replication and mitosis mutually exclusive. MUS81 nuclease is constitutively active throughout the cell cycle but requires association with SLX4 for efficient substrate targeting. To preclude toxic processing of replicating chromosomes, WEE1 kinase restrains CDK1 and PLK1-mediated MUS81-SLX4 assembly during S phase...
December 19, 2016: Developmental Cell
https://www.readbyqxmd.com/read/27984745/rad52-facilitates-mitotic-dna-synthesis-following-replication-stress
#3
Rahul Bhowmick, Sheroy Minocherhomji, Ian D Hickson
Homologous recombination (HR) is necessary to counteract DNA replication stress. Common fragile site (CFS) loci are particularly sensitive to replication stress and undergo pathological rearrangements in tumors. At these loci, replication stress frequently activates DNA repair synthesis in mitosis. This mitotic DNA synthesis, termed MiDAS, requires the MUS81-EME1 endonuclease and a non-catalytic subunit of the Pol-delta complex, POLD3. Here, we examine the contribution of HR factors in promoting MiDAS in human cells...
December 15, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27939696/stc2-as-a-novel-mediator-for-mus81-dependent-proliferation-and-survival-in-hepatocellular-carcinoma
#4
Fan Wu, Ting-Yue Li, Shu-Chao Su, Ji-Shang Yu, Hao-Lu Zhang, Guo-Qian Tan, Jian-Wei Liu, Bai-Lin Wang
Methyl methansulfonate and UV sensitive gene clone 81 (Mus81) is a critical DNA repair gene that has been implicated in development of several cancers including hepatocellular carcinoma (HCC). However, whether Mus81 can affect proliferation and survival of HCC remains unknown. In the present study, we demonstrated that the knockdown of Mus81 was associated with suppressed proliferation and elevated apoptosis of HCC cells in vitro and in vivo. Multilayered screenings, including DNA microarray, high content screen, and real-time PCR validation, identified STC2 as a proliferation-facilitating gene significantly down-regulated in HCC cells upon Mus81 knockdown...
December 8, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27918542/the-role-of-break-induced-replication-in-large-scale-expansions-of-cag-n-ctg-n-repeats
#5
Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah, Sergei M Mirkin
Expansions of (CAG)n/(CTG)n trinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are commonly observed in human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism may lead to a large-scale repeat expansion as a single step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n/(CTG)n repeats in Saccharomyces cerevisiae...
January 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27806301/meiotic-nuclear-oscillations-are-necessary-to-avoid-excessive-chromosome-associations
#6
Mariola R Chacón, Petrina Delivani, Iva M Tolić
Pairing of homologous chromosomes is a crucial step in meiosis, which in fission yeast depends on nuclear oscillations. However, how nuclear oscillations help pairing is unknown. Here, we show that homologous loci typically pair when the spindle pole body is at the cell pole and the nucleus is elongated, whereas they unpair when the spindle pole body is in the cell center and the nucleus is round. Inhibition of oscillations demonstrated that movement is required for initial pairing and that prolonged association of loci leads to mis-segregation...
November 1, 2016: Cell Reports
https://www.readbyqxmd.com/read/27779184/replication-intermediates-that-escape-dna2-activity-are-processed-by-holliday-junction-resolvase-yen1
#7
Gizem Ölmezer, Maryna Levikova, Dominique Klein, Benoît Falquet, Gabriele Alessandro Fontana, Petr Cejka, Ulrich Rass
Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction (HJ) resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination (HR) in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling. Yen1, but not the HJ resolvases Slx1-Slx4 and Mus81-Mms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2...
October 25, 2016: Nature Communications
https://www.readbyqxmd.com/read/27697832/rad51-and-rad54-promote-noncrossover-recombination-between-centromere-repeats-on-the-same-chromatid-to-prevent-isochromosome-formation
#8
Atsushi T Onaka, Naoko Toyofuku, Takahiro Inoue, Akiko K Okita, Minami Sagawa, Jie Su, Takeshi Shitanda, Rei Matsuyama, Faria Zafar, Tatsuro S Takahashi, Hisao Masukata, Takuro Nakagawa
Centromeres consist of DNA repeats in many eukaryotes. Non-allelic homologous recombination (HR) between them can result in gross chromosomal rearrangements (GCRs). In fission yeast, Rad51 suppresses isochromosome formation that occurs between inverted repeats in the centromere. However, how the HR enzyme prevents homology-mediated GCRs remains unclear. Here, we provide evidence that Rad51 with the aid of the Swi/Snf-type motor protein Rad54 promotes non-crossover recombination between centromere repeats to prevent isochromosome formation...
December 15, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27694623/esc2-promotes-mus81-complex-activity-via-its-sumo-like-and-dna-binding-domains
#9
Marek Sebesta, Madhusoodanan Urulangodi, Barbora Stefanovie, Barnabas Szakal, Martin Pacesa, Michael Lisby, Dana Branzei, Lumir Krejci
Replication across damaged DNA templates is accompanied by transient formation of sister chromatid junctions (SCJs). Cells lacking Esc2, an adaptor protein containing no known enzymatic domains, are defective in the metabolism of these SCJs. However, how Esc2 is involved in the metabolism of SCJs remains elusive. Here we show interaction between Esc2 and a structure-specific endonuclease Mus81-Mms4 (the Mus81 complex), their involvement in the metabolism of SCJs, and the effects Esc2 has on the enzymatic activity of the Mus81 complex...
September 30, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27672038/nucleolytic-processing-of-aberrant-replication-intermediates-by-an-exo1-dna2-sae2-axis-counteracts-fork-collapse-driven-chromosome-instability
#10
Arianna Colosio, Camilla Frattini, Grazia Pellicanò, Sara Villa-Hernández, Rodrigo Bermejo
Problems during DNA replication underlie genomic instability and drive malignant transformation. The DNA damage checkpoint stabilizes stalled replication forks thus counteracting aberrant fork transitions, DNA breaks and chromosomal rearrangements. We analyzed fork processing in checkpoint deficient cells by coupling psoralen crosslinking with replication intermediate two-dimensional gel analysis. This revealed a novel role for Exo1 nuclease in resecting reversed replication fork structures and counteracting the accumulation of aberrant intermediates resembling fork cleavage products...
December 15, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27649880/roles-of-eukaryotic-topoisomerases-in-transcription-replication-and-genomic-stability
#11
Yves Pommier, Yilun Sun, Shar-Yin N Huang, John L Nitiss
Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF-ERCC1 and MUS81)...
November 2016: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/27565373/reduced-kinase-activity-of-polo-kinase-cdc5-affects-chromosome-stability-and-dna-damage-response-in-s-cerevisiae
#12
Chetan C Rawal, Sara Riccardo, Chiara Pesenti, Matteo Ferrari, Federica Marini, Achille Pellicioli
Polo-like kinases (PLKs) control several aspects of eukaryotic cell division and DNA damage response. Remarkably, PLKs are overexpressed in several types of cancer, being therefore a marker of bad prognosis. As such, specific PLK kinase activity inhibitors are already used in clinical trials and the regulation of PLK activation is a relevant topic of cancer research. Phosphorylation of threonine residues in the T-loop of the kinase domain is pivotal for PLKs activation. Here, we show that T238A substitution in the T-loop reduces the kinase activity of Cdc5, the only PLK in Saccharomyces cerevisiae, with minor effect on cell growth in unperturbed conditions...
November 2016: Cell Cycle
https://www.readbyqxmd.com/read/27509904/the-nucleolytic-resolution-of-recombination-intermediates-in-yeast-mitotic-cells
#13
Ibtissam Talhaoui, Manuel Bernal, Gerard Mazón
In mitotic cells, the repair of double-strand breaks by homologous recombination (HR) is important for genome integrity. HR requires the orchestration of a subset of pathways for timely removal of joint-molecule intermediates that would otherwise prevent segregation of chromosomes in mitosis. The use of nucleases to resolve recombination intermediates is important for chromosome segregation, but is hazardous because crossovers can result in loss of heterozygosity or chromosome rearrangements. Unregulated use of the nucleases involved in the resolution of recombination intermediates could also be a risk during replication...
September 2016: FEMS Yeast Research
https://www.readbyqxmd.com/read/27434671/small-molecule-inhibitors-identify-the-rad52-ssdna-interaction-as-critical-for-recovery-from-replication-stress-and-for-survival-of-brca2-deficient-cells
#14
Sarah R Hengel, Eva Malacaria, Laura Folly da Silva Constantino, Fletcher E Bain, Andrea Diaz, Brandon G Koch, Liping Yu, Meng Wu, Pietro Pichierri, M Ashley Spies, Maria Spies
The DNA repair protein RAD52 is an emerging therapeutic target of high importance for BRCA-deficient tumors. Depletion of RAD52 is synthetically lethal with defects in tumor suppressors BRCA1, BRCA2 and PALB2. RAD52 also participates in the recovery of the stalled replication forks. Anticipating that ssDNA binding activity underlies the RAD52 cellular functions, we carried out a high throughput screening campaign to identify compounds that disrupt the RAD52-ssDNA interaction. Lead compounds were confirmed as RAD52 inhibitors in biochemical assays...
2016: ELife
https://www.readbyqxmd.com/read/27390022/srs2-and-mus81-mms4-prevent-accumulation-of-toxic-inter-homolog-recombination-intermediates
#15
Kenji Keyamura, Kota Arai, Takashi Hishida
Homologous recombination is an evolutionally conserved mechanism that promotes genome stability through the faithful repair of double-strand breaks and single-strand gaps in DNA, and the recovery of stalled or collapsed replication forks. Saccharomyces cerevisiae ATP-dependent DNA helicase Srs2 (a member of the highly conserved UvrD family of helicases) has multiple roles in regulating homologous recombination. A mutation (srs2K41A) resulting in a helicase-dead mutant of Srs2 was found to be lethal in diploid, but not in haploid, cells...
July 2016: PLoS Genetics
https://www.readbyqxmd.com/read/27383418/gen1-and-eme1-play-redundant-roles-in-dna-repair-and-meiotic-recombination-in-mice
#16
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/27354282/slx4-slx1-protein-independent-down-regulation-of-mus81-eme1-protein-by-hiv-1-viral-protein-r-vpr
#17
Xiaohong Zhou, Maria DeLucia, Jinwoo Ahn
Evolutionarily conserved structure-selective endonuclease MUS81 forms a complex with EME1 and further associates with another endonuclease SLX4-SLX1 to form a four-subunit complex of MUS81-EME1-SLX4-SLX1, coordinating distinctive biochemical activities of both endonucleases in DNA repair. Viral protein R (Vpr), a highly conserved accessory protein in primate lentiviruses, was previously reported to bind SLX4 to mediate down-regulation of MUS81. However, the detailed mechanism underlying MUS81 down-regulation is unclear...
August 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27335459/hiv-1-and-hiv-2-exhibit-divergent-interactions-with-hltf-and-ung2-dna-repair-proteins
#18
Kasia Hrecka, Caili Hao, Ming-Chieh Shun, Sarabpreet Kaur, Selene K Swanson, Laurence Florens, Michael P Washburn, Jacek Skowronski
HIV replication in nondividing host cells occurs in the presence of high concentrations of noncanonical dUTP, apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) cytidine deaminases, and SAMHD1 (a cell cycle-regulated dNTP triphosphohydrolase) dNTPase, which maintains low concentrations of canonical dNTPs in these cells. These conditions favor the introduction of marks of DNA damage into viral cDNA, and thereby prime it for processing by DNA repair enzymes. Accessory protein Vpr, found in all primate lentiviruses, and its HIV-2/simian immunodeficiency virus (SIV) SIVsm paralogue Vpx, hijack the CRL4(DCAF1) E3 ubiquitin ligase to alleviate some of these conditions, but the extent of their interactions with DNA repair proteins has not been thoroughly characterized...
July 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27284361/effect-of-gen1-interference-on-the-chemosensitivity-of-the-breast-cancer-mcf-7-and-skbr3-cell-lines
#19
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/27255997/mus81-is-associated-with-cell-proliferation-and-cisplatin-sensitivity-in-serous-ovarian-cancer
#20
Suhong Xie, Hui Zheng, Xuemei Wen, Jiajun Sun, Yanchun Wang, Xiang Gao, Lin Guo, Renquan Lu
The dysfunction of DNA damage repair (DDR) pathway contributes to tumorigenesis and drug-resistance in cancer. MUS81 is a member of the conserved xeroderma pigmentosum group F (XPF) family protein of endonucleases, which is important to the DDR pathway. However, the role of MUS81 in the development of ovarian cancer remains uncertain. To explore the expression of MUS81 and its association to serous ovarian cancer (SOC), 43 biopsies of SOC patients were detected by qRT-PCR, and 29 specimens were further performed by immunohistochemistry analysis...
August 5, 2016: Biochemical and Biophysical Research Communications
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