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https://www.readbyqxmd.com/read/29156644/akt1-stimulates-homologous-recombination-repair-of-dna-double-strand-breaks-in-a-rad51-dependent-manner
#1
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
https://www.readbyqxmd.com/read/29144403/the-non-homologous-end-joining-protein-paxx-acts-to-restrict-hsv-1-infection
#2
Ben J Trigg, Katharina B Lauer, Paula Fernandes Dos Santos, Heather Coleman, Gabriel Balmus, Daniel S Mansur, Brian J Ferguson
Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection...
November 16, 2017: Viruses
https://www.readbyqxmd.com/read/29136592/human-sirtuin-3-sirt3-deacetylates-histone-h3-lysine-56-to-promote-nonhomologous-end-joining-repair
#3
Amrita Sengupta, Devyani Haldar
Human sirtuin 3 (SIRT3) is a conserved NAD(+) dependent deacetylase, which functions in important cellular processes including transcription, metabolism, oxidative stress response. It is a robust mitochondrial deacetylase; however, few studies have indicated its nuclear functions. Here we report interaction of SIRT3 with core histones and identified acetylated histone H3 lysine 56 (H3K56ac) as its novel substrate, in addition to known substrates acetylated H4K16 and H3K9. Further, we showed in response to DNA damage SIRT3 localizes to the repair foci colocalizing with γH2AX and nonhomologous end joining (NHEJ) marker p53-binding protein 1 (53BP1)...
November 8, 2017: DNA Repair
https://www.readbyqxmd.com/read/29133916/brca2-antagonizes-classical-and-alternative-nonhomologous-end-joining-to-prevent-gross-genomic-instability
#4
Jinhua Han, Chunyan Ruan, Michael S Y Huen, Jiadong Wang, Anyong Xie, Chun Fu, Ting Liu, Jun Huang
BRCA2-deficient cells exhibit gross genomic instability, but the underlying mechanisms are not fully understood. Here we report that inactivation of BRCA2 but not RAD51 destabilizes RPA-coated single-stranded DNA (ssDNA) structures at resected DNA double-strand breaks (DSBs) and greatly enhances the frequency of nuclear fragmentation following cell exposure to DNA damage. Importantly, these BRCA2-associated deficits are fueled by the aberrant activation of classical (c)- and alternative (alt)- nonhomologous end-joining (NHEJ), and rely on the well-defined DNA damage signaling pathway involving the pro-c-NHEJ factor 53BP1 and its downstream effector RIF1...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29128308/oxidative-stress-and-dna-damage-after-cerebral-ischemia-potential-therapeutic-targets-to-preserve-the-genome-and-improve-stroke-recovery
#5
REVIEW
Peiying Li, R Anne Stetler, Rehana K Leak, Yejie Shi, Yan Li, Weifeng Yu, Michael V L Bennett, Jun Chen
The past two decades have witnessed remarkable advances in oxidative stress research, particularly in the context of ischemic brain injury. Oxidative stress in ischemic tissues compromises the integrity of the genome, resulting in DNA lesions, cell death in neurons, glial cells, and vascular cells, and impairments in neurological recovery after stroke. As DNA is particularly vulnerable to oxidative attack, cells have evolved the ability to induce multiple DNA repair mechanisms, including base excision repair (BER), nucleotide excision repair (NER) and non-homogenous endpoint jointing (NHEJ)...
November 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29099045/gene-editing-in-human-lymphoid-cells-role-for-donor-dna-type-of-genomic-nuclease-and-cell-selection-method
#6
Anastasia Zotova, Elena Lopatukhina, Alexander Filatov, Musa Khaitov, Dmitriy Mazurov
Programmable endonucleases introduce DNA breaks at specific sites, which are repaired by non-homologous end joining (NHEJ) or homology recombination (HDR). Genome editing in human lymphoid cells is challenging as these difficult-to-transfect cells may also inefficiently repair DNA by HDR. Here, we estimated efficiencies and dynamics of knockout (KO) and knockin (KI) generation in human T and B cell lines depending on repair template, target loci and types of genomic endonucleases. Using zinc finger nuclease (ZFN), we have engineered Jurkat and CEM cells with the 8...
November 2, 2017: Viruses
https://www.readbyqxmd.com/read/29093183/therapeutic-targeting-of-pgbd5-induced-dna-repair-dependency-in-pediatric-solid-tumors
#7
Anton G Henssen, Casie Reed, Eileen Jiang, Heathcliff Dorado Garcia, Jennifer von Stebut, Ian C MacArthur, Patrick Hundsdoerfer, Jun Hyun Kim, Elisa de Stanchina, Yasumichi Kuwahara, Hajime Hosoi, Neil J Ganem, Filemon Dela Cruz, Andrew L Kung, Johannes H Schulte, John H Petrini, Alex Kentsis
Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma, and Ewing sarcoma, express an active DNA transposase, PGBD5, that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we discovered that mouse and human cells deficient in nonhomologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29091307/expanding-the-crispr-cas9-toolkit-for-pichia-pastoris-with-efficient-donor-integration-and-alternative-resistance-markers
#8
Astrid Weninger, Jasmin Fischer, Hana Raschmanová, Claudia Kniely, Thomas Vogl, Anton Glieder
Komagataella phaffii (syn. Pichia pastoris) is one of the most commonly used host systems for recombinant protein expression. Achieving targeted genetic modifications had been hindered by low frequencies of homologous recombination (HR). Recently, a CRISPR/Cas9 genome editing system has been implemented for P. pastoris enabling gene knockouts based on indels (insertion, deletions) via non-homologous end joining (NHEJ) at near 100% efficiency. However, specifically integrating homologous donor cassettes via HR for replacement studies had proven difficult resulting at most in ∼20% correct integration using CRISPR/Cas9...
November 1, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29078113/tdp1-is-required-for-efficient-non-homologous-end-joining-in-human-cells
#9
Jing Li, Matthew Summerlin, Karin C Nitiss, John L Nitiss, Leslyn A Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3' and 5' terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29077092/paxx-and-xlf-interplay-revealed-by-impaired-cns-development-and-immunodeficiency-of-double-ko-mice
#10
Vincent Abramowski, Olivier Etienne, Ramy Elsaid, Junjie Yang, Aurélie Berland, Laetitia Kermasson, Benoit Roch, Stefania Musilli, Jean-Paul Moussu, Karelia Lipson-Ruffert, Patrick Revy, Ana Cumano, François D Boussin, Jean-Pierre de Villartay
The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions...
October 27, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29065392/cleavage-of-ku80-by-caspase-2-promotes-non-homologous-end-joining-mediated-dna-repair
#11
Qiongyu Yan, Huiqin Zhu, Li Lan, Jing Yi, Jie Yang
Non-homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks (DSBs) requires the formation of a Ku70/Ku80/DNA-PKcs complex at the DSB sites. A previous study has revealed Ku80 cleavage by caspase-3 during apoptosis. However, it remains largely unknown whether and how Ku80 cleavage affects its function in mediating NHEJ-mediated DNA repair. Here we report that Ku80 can be cleaved by caspases-2 at D726 upon a transient etoposide treatment. Caspase-2-mediated Ku80 cleavage promotes Ku80/DNA-PKcs interaction as the D726A mutation diminished Ku80 interaction with DNA-PKcs, while a Ku80 truncate (Ku80 ΔC6) lacking all the 6 residues following D726 rescued the weakened Ku80/DNA-PKcs interaction caused by caspase-2 knockdown...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29059378/characterization-of-the-aplf-fha-xrcc1-phosphopeptide-interaction-and-its-structural-and-functional-implications
#12
Kyungmin Kim, Lars C Pedersen, Thomas W Kirby, Eugene F DeRose, Robert E London
Aprataxin and PNKP-like factor (APLF) is a DNA repair factor containing a forkhead-associated (FHA) domain that supports binding to the phosphorylated FHA domain binding motifs (FBMs) in XRCC1 and XRCC4. We have characterized the interaction of the APLF FHA domain with phosphorylated XRCC1 peptides using crystallographic, NMR, and fluorescence polarization studies. The FHA-FBM interactions exhibit significant pH dependence in the physiological range as a consequence of the atypically high pK values of the phosphoserine and phosphothreonine residues and the preference for a dianionic charge state of FHA-bound pThr...
October 20, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29058711/the-helicase-domain-of-pol%C3%AE-counteracts-rpa-to-promote-alt-nhej
#13
Pedro A Mateos-Gomez, Tatiana Kent, Sarah K Deng, Shane McDevitt, Ekaterina Kashkina, Trung M Hoang, Richard T Pomerantz, Agnel Sfeir
Mammalian polymerase theta (Polθ) is a multifunctional enzyme that promotes error-prone DNA repair by alternative nonhomologous end joining (alt-NHEJ). Here we present structure-function analyses that reveal that, in addition to the polymerase domain, Polθ-helicase activity plays a central role during double-strand break (DSB) repair. Our results show that the helicase domain promotes chromosomal translocations by alt-NHEJ in mouse embryonic stem cells and also suppresses CRISPR-Cas9- mediated gene targeting by homologous recombination (HR)...
October 23, 2017: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29042561/aunip-c1orf135-directs-dna-double-strand-breaks-towards-the-homologous-recombination-repair-pathway
#14
Jiangman Lou, Hongxia Chen, Jinhua Han, Hanqing He, Michael S Y Huen, Xin-Hua Feng, Ting Liu, Jun Huang
DNA double-strand breaks (DSBs) are mainly repaired by either homologous recombination (HR) or non-homologous end-joining (NHEJ). Here, we identify AUNIP/C1orf135, a largely uncharacterized protein, as a key determinant of DSB repair pathway choice. AUNIP physically interacts with CtIP and is required for efficient CtIP accumulation at DSBs. AUNIP possesses intrinsic DNA-binding ability with a strong preference for DNA substrates that mimic structures generated at stalled replication forks. This ability to bind DNA is necessary for the recruitment of AUNIP and its binding partner CtIP to DSBs, which in turn drives CtIP-dependent DNA-end resection and HR repair...
October 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/29018935/a-curious-new-role-for-mrn-in-schizosaccharomyces-pombe-non-homologous-end-joining
#15
REVIEW
Kurt W Runge, Yanhui Li
Chromosomal breaks can be healed by several repair processes, including one called non-homologous end-joining (NHEJ) where the two broken ends are ligated together with a loss of 0-5 bp of DNA. The protein requirements for NHEJ of cut DNA ends in the budding yeast Saccharomyces cerevisiae include its version of the Mre11-Rad50-Nbs1 (MRN) complex. In contrast, the fission yeast Schizosaccharomyces pombe and mammalian cells do not require MRN for this process. Recent work in S. pombe used transposon excision to generate breaks that were capped by DNA hairpins, which must be opened to produce ligatable ends...
October 10, 2017: Current Genetics
https://www.readbyqxmd.com/read/28993682/olaparib-modulates-dna-repair-efficiency-sensitizes-cervical-cancer-cells-to-cisplatin-and-exhibits-anti-metastatic-property
#16
Chandra Bhushan Prasad, Shyam Babu Prasad, Suresh Singh Yadav, Laxmi Kant Pandey, Sunita Singh, Satyajit Pradhan, Gopeshwar Narayan
PARP1 trapping at DNA lesion by pharmacological inhibitors has been exploited in several cancers exhibiting defects in DNA repair mechanisms. PARP1 hyperactivation is involved in therapeutic resistance in multiple cancers. The role of PARP1 in cervical cancer (CC) resistance and implication of PARP inhibitor is yet to be elucidated. Our data demonstrates significantly higher expression of PARP1 in primary cervical tumors and CC cell lines SiHa and ME180. Upon cisplatin treatment CC cells display significant overexpression of PARP1 and its hyperactivation...
October 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28988985/facs-assisted-crispr-cas9-genome-editing-facilitates-parkinson-s-disease-modeling
#17
Jonathan Arias-Fuenzalida, Javier Jarazo, Xiaobing Qing, Jonas Walter, Gemma Gomez-Giro, Sarah Louise Nickels, Holm Zaehres, Hans Robert Schöler, Jens Christian Schwamborn
Genome editing and human induced pluripotent stem cells hold great promise for the development of isogenic disease models and the correction of disease-associated mutations for isogenic tissue therapy. CRISPR-Cas9 has emerged as a versatile and simple tool for engineering human cells for such purposes. However, the current protocols to derive genome-edited lines require the screening of a great number of clones to obtain one free of random integration or on-locus non-homologous end joining (NHEJ)-containing alleles...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28987344/uncharacterized-orf-hur1-influences-the-efficiency-of-non-homologous-end-joining-repair-in-saccharomyces-cerevisiae
#18
Katayoun Omidi, Matthew Jessulat, Mohsen Hooshyar, Daniel Burnside, Andrew Schoenrock, Tom Kazmirchuk, Maryam Hajikarimlou, Mary Daniel, Houman Moteshareie, Urvi Bhojoo, Megan Sanders, Dindial Ramotar, Frank Dehne, Bahram Samanfar, Mohan Babu, Ashkan Golshani
Non-Homologous End Joining (NHEJ) is a highly conserved pathway that repairs Double-Strand Breaks (DSBs) within DNA. Here we show that the deletion of yeast uncharacterized ORF HUR1, Hydroxyurea Resistance1 affects the efficiency of NHEJ. Our findings are supported by Protein-Protein Interaction (PPI), genetic interaction and drug sensitivity analyses. To assess the activity of HUR1 in DSB repair, we deleted its non-overlapping region with PMR1, referred to as HUR1-A. We observed that similar to deletion of TPK1 and NEJ1, and unlike YKU70 (important for NHEJ of DNA with overhang and not blunt end), deletion of HUR1-A reduced the efficiency of NHEJ in both overhang and blunt end plasmid repair assays...
October 4, 2017: Gene
https://www.readbyqxmd.com/read/28985363/protein-phosphatase-1-and-phosphatase-1-nuclear-targeting-subunit-dependent-regulation-of-dna-dependent-protein-kinase-and-non-homologous-end-joining
#19
Songli Zhu, Laura A Fisher, Tadayoshi Bessho, Aimin Peng
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a key role in mediating non-homologous end joining (NHEJ), a major repair pathway for DNA double-strand breaks (DSBs). The activation, function and dynamics of DNA-PKcs is regulated largely by its reversible phosphorylation at numerous residues, many of which are targeted by DNA-PKcs itself. Interestingly, these DNA-PKcs phosphorylation sites function in a distinct, and sometimes opposing manner, suggesting that they are differentially regulated via complex actions of both kinases and phosphatases...
October 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977657/h2ax-facilitates-classical-non-homologous-end-joining-at-the-expense-of-limited-nucleotide-loss-at-repair-junctions
#20
Yi-Li Feng, Ji-Feng Xiang, Si-Cheng Liu, Tao Guo, Guo-Fang Yan, Ye Feng, Na Kong, Hao-Dan Li, Yang Huang, Hui Lin, Xiu-Jun Cai, An-Yong Xie
Phosphorylated histone H2AX, termed 'γH2AX', mediates the chromatin response to DNA double strand breaks (DSBs) in mammalian cells. H2AX deficiency increases the numbers of unrepaired DSBs and translocations, which are partly associated with defects in non-homologous end joining (NHEJ) and contributing to genomic instability in cancer. However, the role of γH2AX in NHEJ of general DSBs has yet to be clearly defined. Here, we showed that despite little effect on overall NHEJ efficiency, H2AX deficiency causes a surprising bias towards accurate NHEJ and shorter deletions in NHEJ products...
October 13, 2017: Nucleic Acids Research
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