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break-induced replication

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https://www.readbyqxmd.com/read/29346668/rad51-and-rtel1-compensate-telomere-loss-in-the-absence-of-telomerase
#1
Margaux Olivier, Cyril Charbonnel, Simon Amiard, Charles I White, Maria E Gallego
Replicative erosion of telomeres is naturally compensated by telomerase and studies in yeast and vertebrates show that homologous recombination can compensate for the absence of telomerase. We show that RAD51 protein, which catalyzes the key strand-invasion step of homologous recombination, is localized at Arabidopsis telomeres in absence of telomerase. Blocking the strand-transfer activity of the RAD51 in telomerase mutant plants results in a strikingly earlier onset of developmental defects, accompanied by increased numbers of end-to-end chromosome fusions...
January 13, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29345572/breaking-the-dna-damage-response-via-serine-threonine-kinase-inhibitors-to-improve-cancer-treatment
#2
Wioletta Rozpedek, Dariusz Pytel, Alicja Nowak-Zdunczyk, Dawid Lewko, Radoslaw Wojtczak, John Alan Diehl, Ireneusz Majsterek
Multiple, both endogenous and exogenous, sources may induce DNA damage and DNA replication stress. Cells have developed DNA damage response (DDR) signaling pathways to maintain genomic stability and effectively detect and repair DNA lesions. Serine/threonine kinases such as Ataxia-telangiectasia mutated (ATM) and Ataxia-telangiectasia and Rad3-Related (ATR) are the major regulators of DDR, since after sensing stalled DNA replication forks, DNA double- or single-strand breaks, may directly phosphorylate and activate their downstream targets, that play a key role in DNA repair, cell cycle arrest and apoptotic cell death...
January 16, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29342113/mitochondria-oxidative-stress-and-the-kynurenine-system-with-a-focus-on-ageing-and-neuroprotection
#3
REVIEW
Katalin Sas, Elza Szabó, László Vécsei
In this review, the potential causes of ageing are discussed. We seek to gain insight into the main physiological functions of mitochondria and discuss alterations in their function and the genome, which are supposed to be the central mechanisms in senescence. We conclude by presenting the potential modulating role of the kynurenine pathway in the ageing processes. Mitochondrial dynamics are supposed to have important physiological roles in maintaining cell homeostasis. During ageing, a decrease in mitochondrial dynamics was reported, potentially compromising the function of mitochondria...
January 17, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29339409/impact-of-homologous-recombination-on-silent-chromatin-in-saccharomyces-cerevisiae
#4
Kathryn J Sieverman, Jasper Rine
Specialized chromatin domains repress transcription of genes within them and present a barrier to many DNA-protein interactions. Silent chromatin in the budding yeast Saccharomyces cerevisiae, akin to heterochromatin of metazoans and plants, inhibits transcription of PolII- and PolIII-transcribed genes, yet somehow grants access to proteins necessary for DNA transactions like replication and homologous recombination. In this study, we adapted a novel assay to detect even transient changes in the dynamics of transcriptional silencing at HML after it served as a template for homologous recombination...
January 16, 2018: Genetics
https://www.readbyqxmd.com/read/29335368/in-medio-stat-virtus-unanticipated-consequences-of-telomere-dysequilibrium
#5
REVIEW
Lea Harrington, Fabio Pucci
The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones...
March 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29320763/a-de-novo-50-bp-gnas-intragenic-duplication-in-a-patient-with-pseudohypoparathyroidism-type-1a
#6
Erina Suzuki, Ryosuke Bo, Kaori Sue, Hiroyuki Awano, Tsutomu Ogata, Satoshi Narumi, Masayo Kagami, Shinichiro Sano, Maki Fukami
Germline intragenic mutations in the GNAS locus result in pseudohypoparathyroidism type 1a (PHP1a) and related conditions. Nearly half of the previously reported GNAS intragenic mutations were structural variants, including 3 tandem duplications of 12-25 bp. However, the precise mutation spectrum and the genomic basis of GNAS structural variants remain to be clarified. Here, we report a de novo 50-bp tandem duplication in GNAS (c.723_772dup50, p.Glu259Leufs*29) identified in a patient with typical clinical features of PHP1a...
January 11, 2018: Cytogenetic and Genome Research
https://www.readbyqxmd.com/read/29312614/3d-structured-illumination-microscopy-reveals-clustered-dna-double-strand-break-formation-in-widespread-%C3%AE-h2ax-foci-after-high-let-heavy-ion-particle-radiation
#7
Yoshihiko Hagiwara, Atsuko Niimi, Mayu Isono, Motohiro Yamauchi, Takaaki Yasuhara, Siripan Limsirichaikul, Takahiro Oike, Hiro Sato, Kathryn D Held, Takashi Nakano, Atsushi Shibata
DNA double-strand breaks (DSBs) induced by ionising radiation are considered the major cause of genotoxic mutations and cell death. While DSBs are dispersed throughout chromatin after X-rays or γ-irradiation, multiple types of DNA damage including DSBs, single-strand breaks and base damage can be generated within 1-2 helical DNA turns, defined as a complex DNA lesion, after high Linear Energy Transfer (LET) particle irradiation. In addition to the formation of complex DNA lesions, recent evidence suggests that multiple DSBs can be closely generated along the tracks of high LET particle irradiation...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29289706/an-engineered-cell-line-lacking-ogg1-and-mutyh-glycosylases-implicates-the-accumulation-of-genomic-8-oxoguanine-as-the-basis-for-paraquat-mutagenicity
#8
Preechaya Tajai, Bogdan I Fedeles, Tawit Suriyo, Panida Navasumrit, Jantamas Kanitwithayanun, John M Essigmann, Jutamaad Satayavivad
Paraquat (1,1'-dimethyl, 4,4'-bipyridinium dichloride; PQ), a widely used herbicide, is toxic to mammals through ingestion, inhalation and skin contact. Epidemiological data suggest that PQ is also mutagenic and carcinogenic, especially in high doses. The toxic and mutagenic properties of PQ are attributed to the ability of the molecule to redox-cycle, which generates reactive oxygen species (ROS) and subsequent oxidative stress. ROS also cause oxidative DNA damage such as 8-oxoguanine (8OG), a mutagenic base that, when replicated, causes G to T transversion mutations...
December 28, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/29247828/hypersensitivity-of-mouse-embryonic-fibroblast-cells-defective-for-dna-polymerases-%C3%AE-%C3%AE-and-%C3%AE%C2%BA-to-various-genotoxic-compounds-its-potential-for-application-in-chemical-genotoxic-screening
#9
Jun-Ichi Akagi, Masayuki Yokoi, Young-Man Cho, Takeshi Toyoda, Haruo Ohmori, Fumio Hanaoka, Kumiko Ogawa
Genotoxic agents cause modifications of genomic DNA, such as alkylation, oxidation, bulky adduct formation, and strand breaks, which potentially induce mutations and changes to the structure or number of genes. Majority of point mutations are generated during error-prone bypass of modified nucleotides (translesion DNA synthesis, TLS); however, when TLS fails, replication forks stalled at lesions eventually result in more lethal effects, formation of double-stranded breaks (DSBs). Here we compared sensitivities to various compounds among mouse embryonic fibroblasts derived from wild-type and knock-out mice lacking one of the three Y-family TLS DNA polymerases (Polη, Polι, and Polκ) or all of them (TKO)...
November 26, 2017: DNA Repair
https://www.readbyqxmd.com/read/29243303/genotoxic-and-mutagenic-properties-of-ni-and-nio-nanoparticles-investigated-by-comet-assay-%C3%AE-h2ax-staining-hprt-mutation-assay-and-toxtracker-reporter-cell-lines
#10
Emma Åkerlund, Francesca Cappellini, Sebastiano Di Bucchianico, Shafiqul Islam, Sara Skoglund, Remco Derr, Inger Odnevall Wallinder, Giel Hendriks, Hanna L Karlsson
Nickel (Ni) compounds are classified as carcinogenic to humans but the underlying mechanisms are still poorly understood. Furthermore, effects related to nanoparticles (NPs) of Ni have not been fully elucidated. The aim of this study was to investigate genotoxicity and mutagenicity of Ni and NiO NPs and compare the effect to soluble Ni from NiCl2 . We employed different models; i.e., exposure of (1) human bronchial epithelial cells (HBEC) followed by DNA strand break analysis (comet assay and γ-H2AX staining); (2) six different mouse embryonic stem (mES) reporter cell lines (ToxTracker) that are constructed to exhibit fluorescence upon the induction of various pathways of relevance for (geno)toxicity and cancer; and (3) mES cells followed by mutagenicity testing (Hprt assay)...
December 15, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/29242289/mild-telomere-dysfunction-as-a-force-for-altering-the-adaptive-potential-of-subtelomeric-genes
#11
Jennifer M O Mason, Michael J McEachern
Subtelomeric regions have several unusual characteristics including complex repetitive structures, increased rates of evolution, and enrichment for genes involved in niche adaptation. The adaptive telomere failure hypothesis suggests that certain environmental stresses can induce a low level of telomere failure, potentially leading to elevated subtelomeric recombination that could result in adaptive mutational changes within subtelomeric genes. Here, we tested a key prediction of the adaptive telomere failure hypothesis; that telomere dysfunction mild enough to have little or no overall effect on cell fitness could still lead to substantial increases in the mutation rates of subtelomeric genes...
December 14, 2017: Genetics
https://www.readbyqxmd.com/read/29234069/the-human-dna-glycosylases-neil1-and-neil3-excise-psoralen-induced-dna-dna-cross-links-in-a-four-stranded-dna-structure
#12
Peter R Martin, Sophie Couvé, Caroline Zutterling, Mustafa S Albelazi, Regina Groisman, Bakhyt T Matkarimov, Jason L Parsons, Rhoderick H Elder, Murat K Saparbaev
Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site-induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29227281/targeting-mcl-1-enhances-dna-replication-stress-sensitivity-to-cancer-therapy
#13
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/29209649/breaking-the-end-target-the-replication-stress-response-at-the-alt-telomeres-for-cancer-therapy
#14
Xiaolei Pan, Naveed Ahmed, Joyce Kong, Dong Zhang
We recently reported that depletion of FANCM in ALT cells induces replication stress mainly at their telomeres. Additionally, we found that co-depletion of FANCM and BLM, or FANCM and BRCA1 induces synthetic lethality in the ALT cells. Our new findings could have important implications for cancer prevention and treatment.
2017: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/29196784/parp1-protects-from-benzo-a-pyrene-diol-epoxide-induced-replication-stress-and-mutagenicity
#15
Jan M F Fischer, Tabea Zubel, Kirsten Jander, Jelena Fix, Irmela R E A Trussina, Daniel Gebhard, Jörg Bergemann, Alexander Bürkle, Aswin Mangerich
Poly(ADP-ribosyl)ation (PARylation) is a complex and reversible posttranslational modification catalyzed by poly(ADP-ribose)polymerases (PARPs), which orchestrates protein function and subcellular localization. The function of PARP1 in genotoxic stress response upon induction of oxidative DNA lesions and strand breaks is firmly established, but its role in the response to chemical-induced, bulky DNA adducts is understood incompletely. To address the role of PARP1 in the response to bulky DNA adducts, we treated human cancer cells with benzo[a]pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE), which represents the active metabolite of the environmental carcinogen benzo[a]pyrene [B(a)P], in nanomolar to low micromolar concentrations...
December 1, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29177742/studying-tdp1-function-in-dna-repair
#16
Shih-Chieh Chiang, Kirsty Liversidge, Sherif F El-Khamisy
Topoisomerase poisons act by inducing abortive topoisomerase reactions, which generate stable protein-DNA breaks (PDBs) that interfere with transcription elongation and progression of replication forks. In vertebrates, Tyrosyl-DNA phosphodiesterase 1 (TDP1) plays a major role in removal of topoisomerase 1-associated PDBs in the nucleus and mitochondria by hydrolyzing the 3'-phosphotyrosine bond. Depletion of TDP1 sensitizes tumor cells with defective DNA repair capacity to the genotoxic effect of TOP1 poisons, while homozygous mutation of the catalytic residue of TDP1 is associated with cerebellar degeneration and ataxia...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29177731/topoisomerase-i-and-genome-stability-the-good-and-the-bad
#17
Jang-Eun Cho, Sue Jinks-Robertson
Topoisomerase I (Top1) resolves torsional stress that accumulates during transcription, replication and chromatin remodeling by introducing a transient single-strand break in DNA. The cleavage activity of Top1 has opposing roles, either promoting or destabilizing genome integrity depending on the context. Resolution of transcription-associated negative supercoils, for example, prevents pairing of the nascent RNA with the DNA template (R-loops) as well as DNA secondary structure formation. Reduced Top1 levels thus enhance CAG repeat contraction, somatic hypermutation, and class switch recombination...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29177481/cdyl1-fosters-double-strand-break-induced-transcription-silencing-and-promotes-homology-directed-repair
#18
Enas R Abu-Zhayia, Samah W Awwad, Bella Ben-Oz, Hanan Khoury-Haddad, Nabieh Ayoub
Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis. DNA damage induction is accompanied by transient transcription repression. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair. We showed that CDYL1 is rapidly recruited to damaged euchromatic regions in a poly [ADP-ribose] polymerase 1 (PARP1)-dependent, but ataxia telangiectasia mutated (ATM)-independent, manner...
November 21, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29176630/break-induced-replication-promotes-formation-of-lethal-joint-molecules-dissolved-by-srs2
#19
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/29162774/the-dna-damage-response-at-dysfunctional-telomeres-and-at-interstitial-and-subtelomeric-dna-double-strand-breaks
#20
Keiko Muraki, John P Murnane
In mammals, DNA double-strand breaks (DSBs) are primarily repaired by classical non-homologous end joining (C-NHEJ), although homologous recombination repair and alternative NHEJ (A-NHEJ), which involve DSB processing, can also occur. These pathways are tightly regulated to maintain chromosome integrity. The ends of chromosomes, called telomeres, contain telomeric DNA that forms a cap structure in cooperation with telomeric proteins to prevent the activation of the DNA damage response and chromosome fusion at chromosome termini...
November 22, 2017: Genes & Genetic Systems
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