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break-induced replication

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https://www.readbyqxmd.com/read/29777036/pol%C3%AE-a-y-family-translesion-synthesis-polymerase-promotes-cellular-tolerance-of-myc-induced-replication-stress
#1
Kiminori Kurashima, Takayuki Sekimoto, Tsukasa Oda, Tsuyoshi Kawabata, Fumio Hanaoka, Takayuki Yamashita
Growth of precancerous and cancer cells relies on their tolerance of oncogene-induced replication stress (RS). Translesion synthesis (TLS) plays an essential role in cellular tolerance of various types of RS and bypasses replication barriers by employing specialized polymerases. However, limited information is available about the role of TLS polymerases in oncogene-induced RS. Here, we report that Polη, a Y-family TLS polymerase, promotes cellular tolerance of Myc-induced RS. Polη was recruited to Myc-induced RS sites, and Polη depletion enhanced the Myc-induced slowing and stalling of replication forks and the subsequent generation of double-strand breaks (DSBs)...
May 18, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29735283/break-induced-replication-the-where-the-why-and-the-how
#2
REVIEW
J Kramara, B Osia, A Malkova
Break-induced replication (BIR) is a pathway that repairs one-ended double-strand breaks (DSBs). For decades, yeast model systems offered the only opportunities to study eukaryotic BIR. These studies described an unusual mode of BIR synthesis that is carried out by a migrating bubble and shows conservative inheritance of newly synthesized DNA, leading to genomic instabilities like those associated with cancer in humans. Yet, evidence of BIR functioning in mammals or during repair of other DNA breaks has been missing...
May 4, 2018: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/29715575/advances-in-therapeutic-targeting-of-the-dna-damage-response-in-cancer
#3
REVIEW
Amar Desai, Yan Yan, Stanton L Gerson
The DNA damage response (DDR) is a series of pathways and processes required to repair lesions to DNA. These pathways range from repairing strand breaks to the double helix, damaged bases formed after oxidation or deamination, inaccurate DNA replication resulting in mispaired base alignment, intrastrand crosslinks that trigger cell death, and a plethora of other genomic insults. The DDR is believed to be a critical component of radio and chemoresistance in many cancers as well, with the tumor's ability to repair therapy induced damage being an important tool used to survive traditional chemotherapeutic agents...
April 23, 2018: DNA Repair
https://www.readbyqxmd.com/read/29712893/linear-mitochondrial-dna-is-rapidly-degraded-by-components-of-the-replication-machinery
#4
Viktoriya Peeva, Daniel Blei, Genevieve Trombly, Sarah Corsi, Maciej J Szukszto, Pedro Rebelo-Guiomar, Payam A Gammage, Alexei P Kudin, Christian Becker, Janine Altmüller, Michal Minczuk, Gábor Zsurka, Wolfram S Kunz
Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5'-3'exonuclease MGME1, elimination of the 3'-5'exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p...
April 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/29710373/transforming-plant-biology-and-breeding-with-crispr-cas9-cas12-and-cas13
#5
REVIEW
Patrick Schindele, Felix Wolter, Holger Puchta
Currently, biology is revolutionized by ever growing applications of the CRISPR/Cas system. As discussed in this Review, new avenues have opened up for plant research and breeding by the use of the sequence-specific DNases Cas9 and Cas12 (formerly named Cpf1) and, more recently, the RNase Cas13 (formerly named C2c2). Although double strand break-induced gene editing based on error-prone non-homologous end joining has been applied to obtain new traits, such as powdery mildew resistance in wheat or improved pathogen resistance and increased yield in tomato, improved technologies based on CRISPR/Cas for programmed change of plant genomes via homologous recombination have recently been developed...
April 30, 2018: FEBS Letters
https://www.readbyqxmd.com/read/29705126/the-mre11a470t-mutation-and-homeologous-interactions-increase-error-prone-bir
#6
In-Joon Baek, Courtney Parke, Arthur J Lustig
In the absence of the RNA-templated reverse transcriptase, telomerase, the predominant means of terminal addition, arises from break-induced replication (BIR) at multiple homologous subtelomeric Y' loci and among internal homeologous (imperfect) (polyG1-3T) tracts. These last tracts are interspersed between subtelomeric Y' direct repeats. One major survivor class contains very short (~50 bp) terminal telomere repeats. This size is sufficient for slow growth and partial telomere functionality and cell viability...
April 26, 2018: Gene
https://www.readbyqxmd.com/read/29676720/mutagenic-repair-of-double-stranded-dna-breaks-in-vaccinia-virus-genomes-requires-cellular-dna-ligase-iv-activity-in-the-cytosol
#7
Rutger David Luteijn, Ingo Drexler, Geoffrey L Smith, Robert Jan Lebbink, Emmanuel J H J Wiertz
Poxviruses comprise a group of large dsDNA viruses that include members relevant to human and animal health, such as variola virus, monkeypox virus, cowpox virus and vaccinia virus (VACV). Poxviruses are remarkable for their unique replication cycle, which is restricted to the cytoplasm of infected cells. The independence from the host nucleus requires poxviruses to encode most of the enzymes involved in DNA replication, transcription and processing. Here, we use the CRISPR/Cas9 genome engineering system to induce DNA damage to VACV (strain Western Reserve) genomes...
April 20, 2018: Journal of General Virology
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
#8
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/29659581/an-interplay-between-multiple-sirtuins-promotes-completion-of-dna-replication-in-cells-with-short-telomeres
#9
Antoine Simoneau, Étienne Ricard, Hugo Wurtele
The evolutionarily-conserved sirtuin family of histone deacetylases regulates a multitude of DNA-associated processes. A recent genome-wide screen conducted in the yeast Saccharomyces cerevisiae identified Yku70/80, which regulate nonhomologous end-joining (NHEJ) and telomere structure, as being essential for cell proliferation in the presence of the pan-sirtuin inhibitor nicotinamide (NAM). Here, we show that sirtuin-dependent deacetylation of both histone H3 lysine 56 and H4 lysine 16 promotes growth of yku70Δ and yku80Δ cells, and that the NAM sensitivity of these mutants is not caused by defects in double-strand break repair by NHEJ, but rather by their inability to maintain normal telomere length...
April 16, 2018: PLoS Genetics
https://www.readbyqxmd.com/read/29649982/identification-and-characterization-of-a-novel-43-bp-deletion-mutation-of-the-atp7b-gene-in-a-chinese-patient-with-wilson-s-disease-a-case-report
#10
Gang Liu, Dingyuan Ma, Jian Cheng, Jingjing Zhang, Chunyu Luo, Yun Sun, Ping Hu, Yuguo Wang, Tao Jiang, Zhengfeng Xu
BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder characterized by copper accumulation. ATP7B gene mutations lead to ATP7B protein dysfunction, which in turn causes Wilson's disease. CASE PRESENTATION: We describe a male case of Wilson's disease diagnosed at 10 years after routine biochemical test that showed low serum ceruloplasmin levels and Kayser-Fleischer rings in both corneas. Analysis of the ATP7B gene revealed compound heterozygous mutations in the proband, including the reported c...
April 12, 2018: BMC Medical Genetics
https://www.readbyqxmd.com/read/29617652/multifaceted-impact-of-microrna-493-5p-on-genome-stabilizing-pathways-induces-platinum-and-parp-inhibitor-resistance-in-brca2-mutated-carcinomas
#11
Khyati Meghani, Walker Fuchs, Alexandre Detappe, Pascal Drané, Ewa Gogola, Sven Rottenberg, Jos Jonkers, Ursula Matulonis, Elizabeth M Swisher, Panagiotis A Konstantinopoulos, Dipanjan Chowdhury
BRCA1/2-mutated ovarian cancers (OCs) are defective in homologous recombination repair (HRR) of double-strand breaks (DSBs) and thereby sensitive to platinum and PARP inhibitors (PARPis). Multiple PARPis have recently received US Food and Drug Administration (FDA) approval for treatment of OCs, and resistance to PARPis is a major clinical problem. Utilizing primary and recurrent BRCA1/2-mutated carcinomas from OC patients, patient-derived lines, and an in vivo BRCA2-mutated mouse model, we identified a microRNA, miR-493-5p, that induced platinum/PARPi resistance exclusively in BRCA2-mutated carcinomas...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29610215/genetic-control-of-genomic-alterations-induced-in-yeast-by-interstitial-telomeric-sequences
#12
Anthony Moore, Margaret Dominska, Patricia Greenwell, Anna Y Aksenova, Sergei Mirkin, Thomas Petes
In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are non-randomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability including terminal inversions (recombination between the ITS and the "true" chromosome telomere) and point mutations in DNA sequences adjacent to the ITS...
April 2, 2018: Genetics
https://www.readbyqxmd.com/read/29605721/combined-inhibition-of-atr-and-wee1-as-a-novel-therapeutic-strategy-in-triple-negative-breast-cancer
#13
Juan Jin, Hehui Fang, Fang Yang, Wenfei Ji, Nan Guan, Zijia Sun, Yaqin Shi, Guohua Zhou, Xiaoxiang Guan
Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti-proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZD6738 can enhance AZD1775-caused growth inhibition in TNBC. Our results show that the enhanced cell death is attributed to repressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage reflected by accumulation of the DNA double-strand-break marker γH2AX...
March 28, 2018: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/29576057/construction-of-a-mutant-of-actinoplanes-sp-n902-109-that-produces-a-new-rapamycin-analog
#14
He Huang, Ping Gao, Qi Zhao, Hai-Feng Hu
In the present study, we introduced point mutations into Ac_rapA which encodes a polyketide synthase responsible for rapamycin biosynthesis in Actinoplanes sp. N902-109, in order to construct a mutant with an inactivated enoylreductase (ER) domain, which was able to synthesize a new rapamycin analog. Based on the homologous recombination induced by double-strand breaks in chromosome mediated by endonuclease I-SceI, the site-directed mutation in the first ER domain of Ac_rapA was introduced using non-replicating plasmid pLYERIA combined with an I-SceI expression plasmid...
March 2018: Chinese Journal of Natural Medicines
https://www.readbyqxmd.com/read/29562185/enteroviruses-remodel-autophagic-trafficking-through-regulation-of-host-snare-proteins-to-promote-virus-replication-and-cell-exit
#15
Abigail K Corona, Holly M Saulsbery, Angel F Corona Velazquez, William T Jackson
Enterovirus D68 (EV-D68) is a medically important respiratory plus-strand RNA virus of children that has been linked to acute flaccid myelitis. We have determined that EV-D68 induces autophagic signaling and membrane formation. Autophagy, a homeostatic degradative process that breaks down protein aggregates and damaged organelles, promotes replication of multiple plus-strand viruses. Induction of autophagic signals promotes EV-D68 replication, but the virus inhibits the downstream degradative steps of autophagy in multiple ways...
March 20, 2018: Cell Reports
https://www.readbyqxmd.com/read/29559578/the-colibactin-genotoxin-generates-dna-interstrand-cross-links-in-infected-cells
#16
Nadège Bossuet-Greif, Julien Vignard, Frédéric Taieb, Gladys Mirey, Damien Dubois, Claude Petit, Eric Oswald, Jean-Philippe Nougayrède
Colibactins are hybrid polyketide-nonribosomal peptides produced by Escherichia coli , Klebsiella pneumoniae , and other Enterobacteriaceae harboring the pks genomic island. These genotoxic metabolites are produced by pks -encoded peptide-polyketide synthases as inactive prodrugs called precolibactins, which are then converted to colibactins by deacylation for DNA-damaging effects. Colibactins are bona fide virulence factors and are suspected of promoting colorectal carcinogenesis when produced by intestinal E...
March 20, 2018: MBio
https://www.readbyqxmd.com/read/29548335/mutational-signatures-reveal-the-role-of-rad52-in-p53-independent-p21-driven-genomic-instability
#17
Panagiotis Galanos, George Pappas, Alexander Polyzos, Athanassios Kotsinas, Ioanna Svolaki, Nickolaos N Giakoumakis, Christina Glytsou, Ioannis S Pateras, Umakanta Swain, Vassilis L Souliotis, Alexandros G Georgakilas, Nicholas Geacintov, Luca Scorrano, Claudia Lukas, Jiri Lukas, Zvi Livneh, Zoi Lygerou, Dipanjan Chowdhury, Claus Storgaard Sørensen, Jiri Bartek, Vassilis G Gorgoulis
BACKGROUND: Genomic instability promotes evolution and heterogeneity of tumors. Unraveling its mechanistic basis is essential for the design of appropriate therapeutic strategies. In a previous study, we reported an unexpected oncogenic property of p21WAF1/Cip1 , showing that its chronic expression in a p53-deficient environment causes genomic instability by deregulation of the replication licensing machinery. RESULTS: We now demonstrate that p21WAF1/Cip1 can further fuel genomic instability by suppressing the repair capacity of low- and high-fidelity pathways that deal with nucleotide abnormalities...
March 16, 2018: Genome Biology
https://www.readbyqxmd.com/read/29531845/expression-of-reca-and-cell-penetrating-peptide-cpp-fusion-protein-in-bacteria-and-in-mammalian-cells
#18
Xiubao Chang, Yuexian Hou
Genome editing is a powerful tool to modify a specific gene and to correct a disease-causing mutation. Recently developed new techniques, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9), significantly facilitate the progression in this field. However, mutations associated with the double strand DNA breaks (DSBs) introduced by these systems hampered their direct usage in clinic. In order to prevent the mutations caused by DSBs, we have designed a novel mean to induce homology-directed recombination (HDR) without DSBs, i...
2018: International Journal of Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29523241/inducing-and-detecting-mitotic-dna-synthesis-at-difficult-to-replicate-loci
#19
Lorenza Garribba, Wei Wu, Özgün Özer, Rahul Bhowmick, Ian D Hickson, Ying Liu
Our conventional understanding of the process of DNA replication is that it occurs in the S-phase of the cell division cycle. However, during investigations into the mechanism by which common fragile sites (CFSs) drive genome instability, we observed that some DNA synthesis was still occurring in early mitosis at these loci. This curious phenomenon of mitotic DNA synthesis (which we now term "MiDAS") appears to be a form of break-induced DNA replication (BIR), a DNA repair process based on homologous recombination that has been characterized in detail only in lower eukaryotes...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29523232/investigation-of-break-induced-replication-in-yeast
#20
Rajula Elango, Zachary Kockler, Liping Liu, Anna Malkova
Break-induced replication (BIR) is an important mechanism aimed to repair one-ended double-strand DNA breaks. BIR is initiated by invasion of a broken DNA end into a homologous template followed by DNA synthesis that can proceed for hundreds of kilobases to the end of the chromosome. Unlike S-phase replication, BIR is carried out by a migrating DNA bubble and is associated with conservative inheritance of newly synthesized DNA. The unusual mode of DNA synthesis during BIR leads to an increased level of genetic instabilities including increased mutagenesis and chromosomal rearrangements...
2018: Methods in Enzymology
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