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https://www.readbyqxmd.com/read/29144403/the-non-homologous-end-joining-protein-paxx-acts-to-restrict-hsv-1-infection
#1
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
#2
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
#3
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/29059378/characterization-of-the-aplf-fha-xrcc1-phosphopeptide-interaction-and-its-structural-and-functional-implications
#4
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
#5
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
#6
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/28987344/uncharacterized-orf-hur1-influences-the-efficiency-of-non-homologous-end-joining-repair-in-saccharomyces-cerevisiae
#7
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
#8
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/28973445/redundancy-between-nucleases-required-for-homologous-recombination-promotes-parp-inhibitor-resistance-in-the-eukaryotic-model-organism-dictyostelium
#9
Anna-Lena Kolb, Alasdair R Gunn, Nicholas D Lakin
ADP-ribosyltransferases promote repair of DNA single strand breaks and disruption of this pathway by Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) is toxic to cells with defects in homologous recombination (HR). Here, we show that this relationship is conserved in the simple eukaryote Dictyostelium and exploit this organism to define mechanisms that drive resistance of the HR-deficient cells to PARPi. Dictyostelium cells disrupted in exonuclease I, a critical factor for HR, are sensitive to PARPi. Deletion of exo1 prevents the accumulation of Rad51 in chromatin induced by PARPi, resulting in DNA damage being channelled through repair by non-homologous end-joining (NHEJ)...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28973441/pol%C3%AE-tumor-variants-decrease-the-efficiency-and-accuracy-of-nhej
#10
Guillermo Sastre-Moreno, John M Pryor, Alberto Díaz-Talavera, José F Ruiz, Dale A Ramsden, Luis Blanco
The non homologous end-joining (NHEJ) pathway of double-strand break (DSB) repair often requires DNA synthesis to fill the gaps generated upon alignment of the broken ends, a complex task performed in human cells by two specialized DNA polymerases, Polλ and Polμ. It is now well established that Polμ is the one adapted to repair DSBs with non-complementary ends, the most challenging scenario, although the structural basis and physiological implications of this adaptation are not fully understood. Here, we demonstrate that two human Polμ point mutations, G174S and R175H, previously identified in two different tumor samples and affecting two adjacent residues, limit the efficiency of accurate NHEJ by Polμ in vitro and in vivo...
September 29, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28963924/efficient-repair-of-dna-double-strand-breaks-in-individuals-from-high-level-natural-radiation-areas-of-kerala-coast-south-west-india
#11
Vinay Jain, Divyalakshmi Saini, P R Vivek Kumar, G Jaikrishan, Birajalaxmi Das
High level natural radiation areas (HLNRA) of Kerala coastal strip (55km long and 0.5km wide) in southwest India exhibit wide variations in the level of background dose (< 1.0-45.0mGy/year) due to thorium deposits in the beach sand. The areas with ≤1.5mGy/year are considered as normal level natural radiation area (NLNRA), whereas areas with >1.5mGy/year are HLNRA. Individuals belonging to HLNRA were stratified into two groups, Low dose group (LDG: 1.51-5.0mGy/year) and high dose group (HDG: >5.0mGy/year)...
September 20, 2017: Mutation Research
https://www.readbyqxmd.com/read/28959974/regulation-of-dna-repair-pathway-choice-in-s-and-g2-phases-by-the-nhej-inhibitor-cyren
#12
Nausica Arnoult, Adriana Correia, Jiao Ma, Anna Merlo, Sara Garcia-Gomez, Marija Maric, Marco Tognetti, Christopher W Benner, Simon J Boulton, Alan Saghatelian, Jan Karlseder
Classical non-homologous end joining (cNHEJ) and homologous recombination compete for the repair of double-stranded DNA breaks during the cell cycle. Homologous recombination is inhibited during the G1 phase of the cell cycle, but both pathways are active in the S and G2 phases. However, it is unclear why cNHEJ does not always outcompete homologous recombination during the S and G2 phases. Here we show that CYREN (cell cycle regulator of NHEJ) is a cell-cycle-specific inhibitor of cNHEJ. Suppression of CYREN allows cNHEJ to occur at telomeres and intrachromosomal breaks during the S and G2 phases, and cells lacking CYREN accumulate chromosomal aberrations upon damage induction, specifically outside the G1 phase...
September 20, 2017: Nature
https://www.readbyqxmd.com/read/28914798/genome-instability-and-%C3%AE-h2ax
#13
REVIEW
Anastasios Georgoulis, Constantinos E Vorgias, George P Chrousos, Emmy P Rogakou
γH2AX has emerged in the last 20 years as a central player in the DDR (DNA damage response), with specificity for DSBs (double-strand breaks). Upon the generation of DSBs, γ-phosphorylation extends along megabase-long domains in chromatin, both sides of the damage. The significance of this mechanism is of great importance; it depicts a biological amplification mechanism where one DSB induces the γ-phosphorylation of thousands of H2AX molecules along megabaselong domains of chromatin, that are adjusted to the sites of DSBs...
September 15, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28912341/the-role-of-blm-helicase-in-homologous-recombination-gene-conversion-tract-length-and-recombination-between-diverged-sequences-in-drosophilamelanogaster
#14
Henry A Ertl, Daniel P Russo, Noori Srivastava, Joseph T Brooks, Thu N Dao, Jeannine R LaRocque
DNA double-strand breaks (DSBs) are a particularly deleterious class of DNA damage that threatens genome integrity. DSBs are repaired by three pathways: nonhomologous-end joining (NHEJ), homologous recombination (HR), and single-strand annealing (SSA). Drosophila melanogaster Blm (DmBlm) is the ortholog of Saccharomyces cerevisiae SGS1 and human BLM, and has been shown to suppress crossovers in mitotic cells and repair mitotic DNA gaps via HR. To further elucidate the role of DmBlm in repair of a simple DSB, and in particular recombination mechanisms, we utilized the Direct Repeat of white (DR-white) and Direct Repeat of whitewith mutations (DR-white...
November 2017: Genetics
https://www.readbyqxmd.com/read/28882611/generation-and-crispr-cas9-editing-of-transformed-progenitor-b-cells-as-a-pseudo-physiological-system-to-study-dna-repair-gene-function-in-v-d-j-recombination
#15
Hélène Lenden Hasse, Chloé Lescale, Joy J Bianchi, Wei Yu, Marie Bedora-Faure, Ludovic Deriano
Antigen receptor gene assembly is accomplished in developing lymphocytes by the V(D)J recombination reaction, which can be separated into two steps: DNA cleavage by the recombination-activating gene (RAG) nuclease and joining of DNA double strand breaks (DSBs) by components of the nonhomologous end joining (NHEJ) pathway. Deficiencies for NHEJ factors can result in immunodeficiency and a propensity to accumulate genomic instability, thus highlighting the importance of identifying all players in this process and deciphering their functions...
September 4, 2017: Journal of Immunological Methods
https://www.readbyqxmd.com/read/28881569/aurora-a-kinase-regulates-non-homologous-end-joining-and-poly-adp-ribose-polymerase-function-in-ovarian-carcinoma-cells
#16
Thuy-Vy Do, Jeff Hirst, Stephen Hyter, Katherine F Roby, Andrew K Godwin
Ovarian cancer is usually diagnosed at late stages when cancer has spread beyond the ovary and patients ultimately succumb to the development of drug-resistant disease. There is an urgent and unmet need to develop therapeutic strategies that effectively treat ovarian cancer and this requires a better understanding of signaling pathways important for ovarian cancer progression. Aurora A kinase (AURKA) plays an important role in ovarian cancer progression by mediating mitosis and chromosomal instability. In the current study, we investigated the role of AURKA in regulating the DNA damage response and DNA repair in ovarian carcinoma cells...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28868264/the-role-of-long-non-coding-rnas-in-the-repair-of-dna-double-strand-breaks
#17
REVIEW
Ali Dianatpour, Soudeh Ghafouri-Fard
DNA double strand breaks (DSBs) are abrasions caused in both strands of the DNA duplex following exposure to both exogenous and endogenous conditions. Such abrasions have deleterious effect in cells leading to genome rearrangements and cell death. A number of repair systems including homologous recombination (HR) and non-homologous end-joining (NHEJ) have been evolved to minimize the fatal effects of these lesions in cell. The role of protein coding genes in regulation of these pathways has been assessed previously...
2017: International Journal of Molecular and Cellular Medicine
https://www.readbyqxmd.com/read/28864683/a-crispr-cas9-based-screening-for-non-homologous-end-joining-inhibitors-reveals-ouabain-and-penfluridol-as-radiosensitizers
#18
Jie Du, Jun Shang, Fei Chen, Yushuo Zhang, Narui Yin, Ting Xie, Haowen Zhang, Jiahua Yu, Fenju Liu
Non-homologous end joining (NHEJ) is the major pathway responsible for the repair of ionizing radiation (IR)-induced DNA double-strand breaks (DSBs), and correspondingly regulates the cellular response to IR. Identification of NHEJ inhibitors could substantially enhance the tumor radiosensitivity and improve the therapeutic efficiency of radiotherapy. In present study, we demonstrated a screening for NHEJ inhibitors by using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and high-resolution melting (HRM) analysis...
September 1, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28855246/localization-of-double-strand-break-repair-proteins-to-viral-replication-compartments-following-lytic-reactivation-of-kaposi-s-sarcoma-associated-herpesvirus
#19
Robert Hollingworth, Richard D Horniblow, Calum Forrest, Grant S Stewart, Roger J Grand
Double-strand breaks (DSBs) in DNA are recognized by the Ku70/80 heterodimer and the MRE11-RAD50-NBS1 (MRN) complex and result in activation of the DNA-PK and ATM kinases, which play key roles in regulating the cellular DNA damage response (DDR). DNA tumor viruses such as Kaposi's sarcoma-associated herpesvirus (KSHV) are known to interact extensively with the DDR during the course of their replicative cycles. Here we show that during lytic amplification of KSHV DNA, the Ku70/80 heterodimer and the MRN complex consistently colocalize with viral genomes in replication compartments (RCs), whereas other DSB repair proteins form foci outside RCs...
November 15, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28846869/xlf-cernunnos-an-important-but-puzzling-participant-in-the-nonhomologous-end-joining-dna-repair-pathway
#20
REVIEW
Vijay Menon, Lawrence F Povirk
DNA double strand breaks (DSBs) are one of the most deleterious DNA lesions that promote cell death, genomic instability and carcinogenesis. The two major cellular mechanisms that repair DSBs are Nonhomologous End-Joining (NHEJ) and Homologous Recombination Repair (HRR). NHEJ is the predominant pathway, in which XLF (also called Cernunnos) is a key player. Patients with XLF mutation exhibit microcephaly, lymphopenia, and growth retardation, and are immunodeficient and radiosensitive. During NHEJ, XLF interacts with XRCC4-Ligase IV, stimulates its ligase activity, and forms DNA-binding filaments of alternating XLF and XRCC4 dimers that may serve to align broken DNA and promote ligation of noncomplementary ends...
October 2017: DNA Repair
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