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homologous dependent recombination

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https://www.readbyqxmd.com/read/29227281/targeting-mcl-1-enhances-dna-replication-stress-sensitivity-to-cancer-therapy
#1
Guo Chen, Andrew T Magis, Ke Xu, Dongkyoo Park, David S Yu, Taofeek K Owonikoko, Gabriel L Sica, Sarah W Satola, Suresh S Ramalingam, Walter J Curran, Paul W Doetsch, Xingming Deng
DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ...
December 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29217771/rad52-is-required-for-rna-templated-recombination-repair-in-post-mitotic-neurons
#2
Starr Welty, Yaqun Teng, Zhuobin Liang, Weixing Zhao, Laurie Sanders, J Timothy Greenamyre, Maria Eulalia Rubio, Amantha Thathiah, Ravindra Kodali, Ronald Wetzel, Arthur S Levine, Li Lan
It has been long assumed that post-mitotic neurons only utilize the error-prone non-homologous end joining (NHEJ) pathway to repair double strand breaks (DSBs) associated with oxidative damage to DNA, given the inability of non-replicating neuronal DNA to utilize a sister chromatid template in the less error-prone homologous recombination (HR) repair pathway. However, we and others recently have found that active transcription triggers a replication-independent recombinational repair mechanism in the G0/G1 phase of the cell cycle...
December 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29211859/transformation-asymmetry-and-the-evolution-of-the-bacterial-accessory-genome
#3
Katinka J Apagyi, Christophe Fraser, Nicholas J Croucher
Bacterial transformation can insert or delete genomic islands (GIs), depending on the donor and recipient genotypes, if an homologous recombination spans the GI's integration site and includes sufficiently long flanking homologous arms. Combining mathematical models of recombination with experiments using pneumococci found GI insertion rates declined geometrically with the GI's size. The decrease in acquisition frequency with length (1.08x10-3 bp-1) was higher than a previous estimate of the analogous rate at which core genome recombinations terminated...
December 1, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/29207996/crispr-cas9-mediated-gene-deletions-in-lager-yeast-saccharomyces-pastorianus
#4
Arthur R Gorter de Vries, Philip A de Groot, Marcel van den Broek, Jean-Marc G Daran
BACKGROUND: The ease of use of CRISPR-Cas9 reprogramming, its high efficacy, and its multiplexing capabilities have brought this technology at the forefront of genome editing techniques. Saccharomyces pastorianus is an aneuploid interspecific hybrid of Saccharomyces cerevisiae and Saccharomyces eubayanus that has been domesticated for centuries and is used for the industrial fermentation of lager beer. For yet uncharacterised reasons, this hybrid yeast is far more resilient to genetic alteration than its ancestor S...
December 5, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/29191918/pml-nuclear-body-disruption-cooperates-in-apl-pathogenesis-and-impairs-dna-damage-repair-pathways-in-mice
#5
Edwige Voisset, Eva Moravcsik, Eva W Stratford, Amie Jaye, Christopher J Palgrave, Robert K Hills, Paolo Salomoni, Scott C Kogan, Ellen Solomon, David Grimwade
A hallmark of acute promyelocytic leukemia (APL) is altered nuclear architecture, with disruption of PML nuclear bodies (NBs) mediated by the PML-RARα oncoprotein. To address whether this phenomenon plays a role in disease pathogenesis, we generated a knock-in mouse model with NB disruption mediated by two point mutations (C62A/C65A) in the Pml RING domain. While no leukemias developed in PmlC62A/C65A mice, these transgenic mice also expressing RARα linked to a dimerization domain (p50-RARα model) exhibited a doubling in the rate of leukemia, with a reduced latency period...
November 30, 2017: Blood
https://www.readbyqxmd.com/read/29180466/synthetic-lethality-of-parp-inhibitors-in-combination-with-myc-blockade-is-independent-of-brca-status-in-triple-negative-breast-cancer
#6
Jason Pw Carey, Cansu Karakas, Tuyen Bui, Xian Chen, Smruthi Vijayaraghavan, Yang Zhao, Jing Wang, Keith Mikule, Jennifer K Litton, Kelly K Hunt, Khandan Keyomarsi
PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival...
November 27, 2017: Cancer Research
https://www.readbyqxmd.com/read/29176980/iragu-a-novel-inducible-and-reversible-mouse-model-for-ubiquitous-recombinase-activity
#7
Marie Bonnet, Leonor Morais Sarmento, Ana C Martins, Daniel Sobral, Joana Silva, Jocelyne Demengeot
Developing lymphocytes express the recombination activating genes (RAGs) 1 and 2 products that form a site specific recombinase complex (RAG), introducing double strand DNA breaks (DSBs) at recombination signal sequences (RSSs) flanking the V, D, and J gene segments in the antigen receptor loci. The subsequent steps in the reaction consist in the ligation of DSBs by ubiquitous enzymes of the non-homologous end joining DNA repair pathway. This mutagenesis process is responsible for the generation of the very large clonal diversity of T and B lymphocytes, itself allowing the recognition of a virtually open-ended antigenic universe...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29176810/flip-flop-mating-type-switching-in-the-methylotrophic-yeast-ogataea-polymorpha-is-regulated-by-an-efg1-rme1-ste12-pathway
#8
Sara J Hanson, Kevin P Byrne, Kenneth H Wolfe
In haploid cells of Ogataea (Hansenula) polymorpha an environmental signal, nitrogen starvation, induces a reversible change in the structure of a chromosome. This process, mating-type switching, inverts a 19-kb DNA region to place either MATa or MATα genes under centromeric repression of transcription, depending on the orientation of the region. Here, we investigated the genetic pathway that controls switching. We characterized the transcriptomes of haploid and diploid O. polymorpha by RNAseq in rich and nitrogen-deficient media, and found that there are no constitutively a-specific or α-specific genes other than the MAT genes themselves...
November 27, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29175904/cohesin-sa2-is-a-sequence-independent-dna-binding-protein-that-recognizes-dna-replication-and-repair-intermediates
#9
Preston Countryman, Yanlin Fan, Aparna Gorthi, Hai Pan, Jack Strickland, Parminder Kaur, Xuechun Wang, Jianggguo Lin, Xiaoying Lei, Christian White, Changjiang You, Nicolas Wirth, Ingrid Tessmer, Jacob Pieler, Robert Riehn, Alexander J R Bishop, Yizhi Jane Tao, Hong Wang
Proper chromosome alignment and segregation during mitosis depend on cohesion between sister chromatids, mediated by the cohesin protein complex, which also plays crucial roles in diverse genome maintenance pathways. Current models attribute DNA binding by cohesin to entrapment of dsDNA by the cohesin ring subunits (SMC1, SMC3, and RAD21 in humans). However, the biophysical properties and activities of the fourth core cohesin subunit SA2 (STAG2) are largely unknown. Here, using single molecule atomic force and fluorescence microscopy imaging as well as fluorescence anisotropy measurements, we established that SA2 binds to both dsDNA and ssDNA, albeit with a higher binding affinity for ssDNA...
November 24, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29174433/novel-chimeric-parapoxvirus-cf189-as-an-oncolytic-immunotherapy-in-triple-negative-breast-cancer
#10
Audrey H Choi, Michael P O'Leary, Shyambabu Chaurasiya, Jianming Lu, Sang-In Kim, Yuman Fong, Nanhai G Chen
BACKGROUND: Triple-negative breast cancer is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here we describe a novel, genetically engineered parapoxvirus that efficiently kills triple-negative breast cancer. METHODS: A novel chimeric parapoxvirus (CF189) was generated via homologous recombination and identified through high-throughput screening. Cytotoxicity was assayed in vitro in 4 triple-negative breast cancer cell lines...
November 22, 2017: Surgery
https://www.readbyqxmd.com/read/29173172/therapeutic-applications-of-crispr-cas-for-duchenne-muscular-dystrophy
#11
Tatianna Wai Ying Wong, Ronald D Cohn
BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by the lack of dystrophin due to mutations in the DMD gene. Since dystrophin is essential in maintaining the integrity of the sarcolemmal membrane, the absence of the protein leads to muscle damage and DMD disease manifestation. Currently there is no cure with only symptomatic management available. OBJECTIVE: The most recent advancements in DMD therapies do not provide a permanent treatment for DMD...
November 21, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/29171451/sequence-homology-and-expression-profile-of-genes-associated-with-dna-repair-pathways-in-mycobacterium-leprae
#12
Mukul Sharma, Sundeep Chaitanya Vedithi, Madhusmita Das, Anindya Roy, Mannam Ebenezer
BACKGROUND: Survival of Mycobacterium leprae, the causative bacteria for leprosy, in the human host is dependent to an extent on the ways in which its genome integrity is retained. DNA repair mechanisms protect bacterial DNA from damage induced by various stress factors. The current study is aimed at understanding the sequence and functional annotation of DNA repair genes in M. leprae. METHODS: T he genome of M. leprae was annotated using sequence alignment tools to identify DNA repair genes that have homologs in Mycobacterium tuberculosis and Escherichia coli...
October 2017: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/29170977/species-differences-and-mechanism-of-action-of-a3-adenosine-receptor-allosteric-modulators
#13
Lili Du, Zhan-Guo Gao, Silvia Paoletta, Tina C Wan, Elizabeth T Gizewski, Samantha Barbour, Jacobus P D van Veldhoven, Adriaan P IJzerman, Kenneth A Jacobson, John A Auchampach
Activity of the A3 adenosine receptor (AR) allosteric modulators LUF6000 (2-cyclohexyl-N-(3,4-dichlorophenyl)-1H-imidazo [4,5-c]quinolin-4-amine) and LUF6096 (N-{2-[(3,4-dichlorophenyl)amino]quinolin-4-yl}cyclohexanecarbox-amide) was compared at four A3AR species homologs used in preclinical drug development. In guanosine 5'-[γ-[(35)S]thio]triphosphate ([(35)S]GTPγS) binding assays with cell membranes isolated from human embryonic kidney cells stably expressing recombinant A3ARs, both modulators substantially enhanced agonist efficacy at human, dog, and rabbit A3ARs but provided only weak activity at mouse A3ARs...
November 23, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/29170962/coupling-yeast-golden-gate-and-vegas-for-efficient-assembly-of-the-violacein-pathway-in-saccharomyces-cerevisiae
#14
James Chuang, Jef D Boeke, Leslie A Mitchell
The ability to express non-native pathways in genetically tractable model systems is important for fields such as synthetic biology, genetics, and metabolic engineering. Here we describe a modular and hierarchical strategy to assemble multigene pathways for expression in S. cerevisiae. First, discrete promoter, coding sequence, and terminator parts are assembled in vitro into Transcription Units (TUs) flanked by adapter sequences using "yeast Golden Gate" (yGG), a type IIS restriction enzyme-dependent cloning strategy...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29167439/eroded-telomeres-are-rearranged-in-quiescent-fission-yeast-cells-through-duplications-of-subtelomeric-sequences
#15
Laetitia Maestroni, Julien Audry, Samah Matmati, Benoit Arcangioli, Vincent Géli, Stéphane Coulon
While the mechanisms of telomere maintenance has been investigated in dividing cells, little is known about the stability of telomeres in quiescent cells and how dysfunctional telomeres are processed in non-proliferating cells. Here we examine the stability of telomeres in quiescent cells using fission yeast. While wild type telomeres are stable in quiescence, we observe that eroded telomeres were highly rearranged during quiescence in telomerase minus cells. These rearrangements depend on homologous recombination (HR) and correspond to duplications of subtelomeric regions...
November 22, 2017: Nature Communications
https://www.readbyqxmd.com/read/29163580/testing-of-auxotrophic-selection-markers-for-use-in-the-moss-physcomitrella-provides-new-insights-into-the-mechanisms-of-targeted-recombination
#16
Mikael Ulfstedt, Guo-Zhen Hu, Monika Johansson, Hans Ronne
The moss Physcomitrella patens is unique among plants in that homologous recombination can be used to knock out genes, just like in yeast. Furthermore, transformed plasmids can be rescued from Physcomitrella back into Escherichia coli, similar to yeast. In the present study, we have tested if a third important tool from yeast molecular genetics, auxotrophic selection markers, can be used in Physcomitrella. Two auxotrophic moss strains were made by knocking out the PpHIS3 gene encoding imidazoleglycerol-phosphate dehydratase, and the PpTRP1 gene encoding phosphoribosylanthranilate isomerase, disrupting the biosynthesis of histidine and tryptophan, respectively...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29162700/double-strand-dna-breaks-are-mainly-repaired-by-the-homologous-recombination-pathway-in-early-developing-swine-embryos
#17
Rodrigo C Bohrer, Naomi Dicks, Karina Gutierrez, Raj Duggavathi, Vilceu Bordignon
DNA double-strand breaks (DSBs) are less frequent than single-strand breaks but have more harmful consequences on cell survival and physiology. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two main pathways that are responsible for DSB repair in eukaryotic cells, but their importance for the preservation of genome stability in totipotent blastomeres of early developing embryos has not been determined. In this study, we observed that the chemical inhibition of HR or both pathways, but not NHEJ alone, increased the number of DSBs, reduced embryo development to the blastocyst stage, and resulted in embryos with higher proportions of apoptotic cells...
November 21, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29162625/sgs1-binding-to-rad51-stimulates-homology-directed-dna-repair-in-saccharomyces-cerevisiae
#18
Lillian Campos-Doerfler, Salahuddin Syed, Kristina H Schmidt
Accurate repair of DNA breaks is essential for maintaining genome integrity and cellular fitness. Sgs1, the sole member of the RecQ family of DNA helicases in Saccharomyces cerevisiae, is important for both early and late stages of homology-dependent repair. Its large number of physical and genetic interactions with DNA recombination, repair and replication factors has established Sgs1 as a key player in the maintenance of genome integrity. To determine the significance of Sgs1 binding to the strand exchange factor Rad51 we have identified a single amino acid change C-terminal of the helicase core of Sgs1 that disrupts Rad51 binding...
November 21, 2017: Genetics
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
#19
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...
November 21, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29156644/akt1-stimulates-homologous-recombination-repair-of-dna-double-strand-breaks-in-a-rad51-dependent-manner
#20
Katharina Mueck, Simone Rebholz, Mozhgan Dehghan Harati, H Peter Rodemann, Mahmoud Toulany
Akt1 is known to promote non-homologous end-joining (NHEJ)-mediated DNA double-strand break (DSB) repair by stimulation of DNA-PKcs. In the present study, we investigated the effect of Akt1 on homologous recombination (HR)-dependent repair of radiation-induced DSBs in non-small cell lung cancer (NSCLC) cells A549 and H460. Akt1-knockdown (Akt1-KD) significantly reduced Rad51 protein level, Rad51 foci formation and its colocalization with γH2AX foci after irradiation. Moreover, Akt1-KD decreased clonogenicity after treatment with Mitomycin C and HR repair, as tested by an HR-reporter assay...
November 20, 2017: International Journal of Molecular Sciences
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