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https://www.readbyqxmd.com/read/29662610/human-cancer-cells-utilize-mitotic-dna-synthesis-to-resist-replication-stress-at-telomeres-regardless-of-their-telomere-maintenance-mechanism
#1
Özgün Özer, Rahul Bhowmick, Ying Liu, Ian D Hickson
Telomeres resemble common fragile sites (CFSs) in that they are difficult-to-replicate and exhibit fragility in mitosis in response to DNA replication stress. At CFSs, this fragility is associated with a delay in the completion of DNA replication until early mitosis, whereupon cells are proposed to switch to a RAD52-dependent form of break-induced replication. Here, we show that this mitotic DNA synthesis (MiDAS) is also a feature of human telomeres. Telomeric MiDAS is not restricted to those telomeres displaying overt fragility, and is a feature of a wide range of cell lines irrespective of whether their telomeres are maintained by telomerase or by the alternative lengthening of telomeres (ALT) mechanism...
March 23, 2018: Oncotarget
https://www.readbyqxmd.com/read/29622660/rnase-h-eliminates-r-loops-that-disrupt-dna-replication-but-is-nonessential-for-efficient-dsb-repair
#2
Hongchang Zhao, Min Zhu, Oliver Limbo, Paul Russell
In Saccharomyces cerevisiae , genome stability depends on RNases H1 and H2, which remove ribonucleotides from DNA and eliminate RNA-DNA hybrids (R-loops). In Schizosaccharomyces pombe , RNase H enzymes were reported to process RNA-DNA hybrids produced at a double-strand break (DSB) generated by I-PpoI meganuclease. However, it is unclear if RNase H is generally required for efficient DSB repair in fission yeast, or whether it has other genome protection roles. Here, we show that S. pombe rnh1∆ rnh201∆ cells, which lack the RNase H enzymes, accumulate R-loops and activate DNA damage checkpoints...
April 5, 2018: EMBO Reports
https://www.readbyqxmd.com/read/29577315/the-recq-like-helicase-hrq1-is-involved-in-dna-crosslink-repair-in-arabidopsis-in-a-common-pathway-with-the-fanconi-anemia-associated-nuclease-fan1-and-the-postreplicative-repair-atpase-rad5a
#3
Sarah Röhrig, Annika Dorn, Janina Enderle, Angelina Schindele, Natalie J Herrmann, Alexander Knoll, Holger Puchta
RecQ helicases are important caretakers of genome stability and occur in varying copy numbers in different eukaryotes. Subsets of RecQ paralogs are involved in DNA crosslink (CL) repair. The orthologs of AtRECQ2, AtRECQ3 and AtHRQ1, HsWRN, DmRECQ5 and ScHRQ1 participate in CL repair in their respective organisms, and we aimed to define the function of these helicases for plants. We obtained Arabidopsis mutants of the three RecQ helicases and determined their sensitivity against CL agents in single- and double-mutant analyses...
March 25, 2018: New Phytologist
https://www.readbyqxmd.com/read/29414053/collaboration-in-the-actions-of-brh2-with-resolving-functions-during-dna-repair-and-replication-stress-in-ustilago-maydis
#4
Milorad Kojic, Mira Milisavljevic, William K Holloman
Cells maintain a small arsenal of resolving functions to process and eliminate complex DNA intermediates that result as a consequence of homologous recombination and distressed replication. Ordinarily the homologous recombination system serves as a high-fidelity mechanism to restore the integrity of a damaged genome, but in the absence of the appropriate resolving function it can turn DNA intermediates resulting from replication stress into pathological forms that are toxic to cells. Here we have investigated how the nucleases Mus81 and Gen1 and the helicase Blm contribute to survival after DNA damage or replication stress in Ustilago maydis cells with crippled yet homologous recombination-proficient forms of Brh2, the BRCA2 ortholog and primary Rad51 mediator...
February 2, 2018: DNA Repair
https://www.readbyqxmd.com/read/29393493/inhibition-of-mus81-improves-the-chemical-sensitivity-of-olaparib-by-regulating-mcm2-in-epithelial-ovarian-cancer
#5
Ailing Zhong, Hongqin Zhang, Suhong Xie, Minjie Deng, Hui Zheng, Yanchun Wang, Miaomiao Chen, Renquan Lu, Lin Guo
Dysfunction of the DNA repair pathway contributes to tumorigenesis and drug resistance. Methyl methanesulfonate and ultraviolet sensitive gene clone 81 (MUS81), a key endonuclease in DNA repair, is generally considered a tumor suppressor; however, recent studies have revealed its tumor-promoting effect in epithelial ovarian cancer (EOC) and have shown that its overexpression is associated with cisplatin sensitization. However, the exact functional role of MUS81 and its regulation in relation to chemotherapy sensitivity remains unknown...
January 22, 2018: Oncology Reports
https://www.readbyqxmd.com/read/29352063/-arabidopsis-thaliana-fancd2-promotes-meiotic-crossover-formation
#6
Marie-Therese Kurzbauer, Mónica Pradillo, Claudia Kerzendorfer, Jason Sims, Rene Ladurner, Cecilia Oliver, Michael Peter Janisiw, Magdalena Mosiolek, Dieter Schweizer, Gregory P Copenhaver, Peter Schlögelhofer
Fanconi anemia (FA) is a human autosomal recessive disorder characterized by chromosomal instability, developmental pathologies, predisposition to cancer, and reduced fertility. So far, 19 genes have been implicated in FA, most of them involved in DNA repair. Some are conserved across higher eukaryotes, including plants. The Arabidopsis thaliana genome encodes a homolog of the Fanconi anemia D2 gene ( FANCD2 ) whose function in DNA repair is not yet fully understood. Here, we provide evidence that At FANCD2 is required for meiotic homologous recombination...
February 2018: Plant Cell
https://www.readbyqxmd.com/read/29348327/genome-instability-as-a-consequence-of-defects-in-the-resolution-of-recombination-intermediates
#7
Stephen C West, Ying Wai Chan
The efficient processing of homologous recombination (HR) intermediates, which often contain four-way structures known as Holliday junctions (HJs), is required for proper chromosome segregation at mitosis. Eukaryotic cells possess three distinct pathways of resolution: (i) HJ dissolution mediated by BLM-topoisomerase IIIα-RMI1-RMI2 (BTR) complex, and HJ resolution catalyzed by either (ii) SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX complex) or (iii) GEN1. The BTR pathway acts at all times throughout the cell cycle, whereas the actions of SMX and GEN1 are restrained in S phase and become elevated late in the cell cycle to ensure the resolution of persistent recombination intermediates before mitotic division...
January 18, 2018: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/29176630/break-induced-replication-promotes-formation-of-lethal-joint-molecules-dissolved-by-srs2
#8
Rajula Elango, Ziwei Sheng, Jessica Jackson, Jenna DeCata, Younis Ibrahim, Nhung T Pham, Diana H Liang, Cynthia J Sakofsky, Alessandro Vindigni, Kirill S Lobachev, Grzegorz Ira, Anna Malkova
Break-induced replication (BIR) is a DNA double-strand break repair pathway that leads to genomic instabilities similar to those observed in cancer. BIR proceeds by a migrating bubble where asynchrony between leading and lagging strand synthesis leads to accumulation of long single-stranded DNA (ssDNA). It remains unknown how this ssDNA is prevented from unscheduled pairing with the template, which can lead to genomic instability. Here, we propose that uncontrolled Rad51 binding to this ssDNA promotes formation of toxic joint molecules that are counteracted by Srs2...
November 27, 2017: Nature Communications
https://www.readbyqxmd.com/read/29072253/corrigendum-mus81-nuclease-activity-is-essential-for-replication-stress-tolerance-and-chromosome-segregation-in-brca2-deficient-cells
#9
Xianning Lai, Ronan Broderick, Valérie Bergoglio, Jutta Zimmer, Sophie Badie, Wojciech Niedzwiedz, Jean-Sébastien Hoffmann, Madalena Tarsounas
This corrects the article DOI: 10.1038/ncomms15983.
October 26, 2017: Nature Communications
https://www.readbyqxmd.com/read/29038425/mre11-and-exo1-nucleases-degrade-reversed-forks-and-elicit-mus81-dependent-fork-rescue-in-brca2-deficient-cells
#10
Delphine Lemaçon, Jessica Jackson, Annabel Quinet, Joshua R Brickner, Shan Li, Stephanie Yazinski, Zhongsheng You, Grzegorz Ira, Lee Zou, Nima Mosammaparast, Alessandro Vindigni
The breast cancer susceptibility proteins BRCA1 and BRCA2 have emerged as key stabilizing factors for the maintenance of replication fork integrity following replication stress. In their absence, stalled replication forks are extensively degraded by the MRE11 nuclease, leading to chemotherapeutic sensitivity. Here we report that BRCA proteins prevent nucleolytic degradation by protecting replication forks that have undergone fork reversal upon drug treatment. The unprotected regressed arms of reversed forks are the entry point for MRE11 in BRCA-deficient cells...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29035360/ezh2-promotes-degradation-of-stalled-replication-forks-by-recruiting-mus81-through-histone-h3-trimethylation
#11
Beatrice Rondinelli, Ewa Gogola, Hatice Yücel, Alexandra A Duarte, Marieke van de Ven, Roxanne van der Sluijs, Panagiotis A Konstantinopoulos, Jos Jonkers, Raphaël Ceccaldi, Sven Rottenberg, Alan D D'Andrea
The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease...
November 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28988007/chromosome-copy-number-variation-in-telomerized-human-bone-marrow-stromal-cells-insights-for-monitoring-safe-ex-vivo-expansion-of-adult-stem-cells
#12
Jorge S Burns, Linda Harkness, Abdullah Aldahmash, Laurent Gautier, Moustapha Kassem
Adult human bone marrow stromal cells (hBMSC) cultured for cell therapy require evaluation of potency and stability for safe use. Chromosomal aberrations upsetting genomic integrity in such cells have been contrastingly described as "Limited" or "Significant". Previously reported stepwise acquisition of a spontaneous neoplastic phenotype during three-year continuous culture of telomerized cells (hBMSC-TERT20) didn't alter a diploid karyotype measured by spectral karyotype analysis (SKY)...
December 2017: Stem Cell Research
https://www.readbyqxmd.com/read/28969641/role-of-pcna-and-rfc-in-promoting-mus81-complex-activity
#13
Alexandra Sisakova, Veronika Altmannova, Marek Sebesta, Lumir Krejci
BACKGROUND: Proper DNA replication is essential for faithful transmission of the genome. However, replication stress has serious impact on the integrity of the cell, leading to stalling or collapse of replication forks, and has been determined as a driving force of carcinogenesis. Mus81-Mms4 complex is a structure-specific endonuclease previously shown to be involved in processing of aberrant replication intermediates and promotes POLD3-dependent DNA synthesis via break-induced replication...
October 2, 2017: BMC Biology
https://www.readbyqxmd.com/read/28922417/lingering-single-strand-breaks-trigger-rad51-independent-homology-directed-repair-of-collapsed-replication-forks-in-the-polynucleotide-kinase-phosphatase-mutant-of-fission-yeast
#14
Arancha Sanchez, Mariana C Gadaleta, Oliver Limbo, Paul Russell
The DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) protects genome integrity by restoring ligatable 5'-phosphate and 3'-hydroxyl termini at single-strand breaks (SSBs). In humans, PNKP mutations underlie the neurological disease known as MCSZ, but these individuals are not predisposed for cancer, implying effective alternative repair pathways in dividing cells. Homology-directed repair (HDR) of collapsed replication forks was proposed to repair SSBs in PNKP-deficient cells, but the critical HDR protein Rad51 is not required in PNKP-null (pnk1Δ) cells of Schizosaccharomyces pombe...
September 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28813668/subnuclear-relocalization-of-structure-specific-endonucleases-in-response-to-dna-damage
#15
Irene Saugar, Alberto Jiménez-Martín, José Antonio Tercero
Structure-specific endonucleases contribute to the maintenance of genome integrity by cleaving DNA intermediates that need to be resolved for faithful DNA repair, replication, or recombination. Despite advances in the understanding of their function and regulation, it is less clear how these proteins respond to genotoxic stress. Here, we show that the structure-specific endonuclease Mus81-Mms4/EME1 relocalizes to subnuclear foci following DNA damage and colocalizes with the endonucleases Rad1-Rad10 (XPF-ERCC1) and Slx1-Slx4...
August 15, 2017: Cell Reports
https://www.readbyqxmd.com/read/28781165/multi-invasions-are-recombination-byproducts-that-induce-chromosomal-rearrangements
#16
Aurèle Piazza, William Douglass Wright, Wolf-Dietrich Heyer
Inaccurate repair of broken chromosomes generates structural variants that can fuel evolution and inflict pathology. We describe a novel rearrangement mechanism in which translocation between intact chromosomes is induced by a lesion on a third chromosome. This multi-invasion-induced rearrangement (MIR) stems from a homologous recombination byproduct, where a broken DNA end simultaneously invades two intact donors. No homology is required between the donors, and the intervening sequence from the invading molecule is inserted at the translocation site...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28714477/mus81-nuclease-activity-is-essential-for-replication-stress-tolerance-and-chromosome-segregation-in-brca2-deficient-cells
#17
Xianning Lai, Ronan Broderick, Valérie Bergoglio, Jutta Zimmer, Sophie Badie, Wojciech Niedzwiedz, Jean-Sébastien Hoffmann, Madalena Tarsounas
Failure to restart replication forks stalled at genomic regions that are difficult to replicate or contain endogenous DNA lesions is a hallmark of BRCA2 deficiency. The nucleolytic activity of MUS81 endonuclease is required for replication fork restart under replication stress elicited by exogenous treatments. Here we investigate whether MUS81 could similarly facilitate DNA replication in the context of BRCA2 abrogation. Our results demonstrate that replication fork progression in BRCA2-deficient cells requires MUS81...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28645372/analysis-of-structure-selective-endonuclease-activities-from-yeast-and-human-extracts
#18
Joao Matos, Stephen C West
The efficient separation of two equal DNA masses to the daughter cells is an essential step in mitosis. This process is dependent upon the removal of any remaining recombination or replication intermediates that link sister chromatids, and a failure to resolve these intermediates leads to genome instability. Similarly, a failure to resolve meiotic recombination intermediates that link homologous chromosomes can cause chromosome nondisjunction and aneuploidy. Cleavage of these potentially toxic replication/recombination intermediates requires the Mus81 endonuclease, which is active upon flaps, forks, and more complex secondary structures in DNA such as Holliday junctions...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28640495/control-of-mus81-nuclease-during-the-cell-cycle
#19
REVIEW
Boris Pfander, Joao Matos
DNA replication and homologous recombination involve the formation of branched DNA structures that physically link chromosomes. Such DNA-based connections, which arise during S-phase, are typically disengaged prior to entry into mitosis, in order to ensure proper chromosome segregation. Exceptions can, however, occur: replication stress, or elevated levels of DNA damage, may cause cells to enter mitosis with unfinished replication as well as carrying recombination intermediates, such as Holliday junctions. Hence, cells are equipped with pathways that recognize and process branched DNA structures, and evolved mechanisms to enhance their function when on the verge of undergoing cell division...
July 2017: FEBS Letters
https://www.readbyqxmd.com/read/28586299/inter-fork-strand-annealing-causes-genomic-deletions-during-the-termination-of-dna-replication
#20
Carl A Morrow, Michael O Nguyen, Andrew Fower, Io Nam Wong, Fekret Osman, Claire Bryer, Matthew C Whitby
Problems that arise during DNA replication can drive genomic alterations that are instrumental in the development of cancers and many human genetic disorders. Replication fork barriers are a commonly encountered problem, which can cause fork collapse and act as hotspots for replication termination. Collapsed forks can be rescued by homologous recombination, which restarts replication. However, replication restart is relatively slow and, therefore, replication termination may frequently occur by an active fork converging on a collapsed fork...
June 6, 2017: ELife
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