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https://www.readbyqxmd.com/read/29348879/loss-of-neil3-dna-glycosylase-markedly-increases-replication-associated-double-strand-breaks-and-enhances-sensitivity-to-atr-inhibitor-in-glioblastoma-cells
#1
Alex W Klattenhoff, Megha Thakur, Christopher S Chu, Debolina Ray, Samy L Habib, Dawit Kidane
DNA endonuclease eight-like glycosylase 3 (NEIL3) is one of the DNA glycosylases that removes oxidized DNA base lesions from single-stranded DNA (ssDNA) and non-B DNA structures. Approximately seven percent of human tumors have an altered NEIL3 gene. However, the role of NEIL3 in replication-associated repair and its impact on modulating treatment response is not known. Here, we report that NEIL3 is localized at the DNA double-strand break (DSB) sites during oxidative DNA damage and replication stress. Loss of NEIL3 significantly increased spontaneous replication-associated DSBs and recruitment of replication protein A (RPA)...
December 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29346668/rad51-and-rtel1-compensate-telomere-loss-in-the-absence-of-telomerase
#2
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/29340034/prexasertib-a-cell-cycle-checkpoint-kinases-1-and-2-inhibitor-increases-in-vitro-toxicity-of-parp-inhibition-by-preventing-rad51-foci-formation-in-brca-wild-type-high-grade-serous-ovarian-cancer
#3
Ethan Brill, Takuhei Yokoyama, Jayakumar Nair, Minshu Yu, Yeong-Ran Ahn, Jung-Min Lee
PARP inhibitors (PARPi) have been effective in high-grade serous ovarian cancer (HGSOC), although clinical activity is limited against BRCA wild type HGSOC. The nearly universal loss of normal p53 regulation in HGSOCs causes dysfunction in the G1/S checkpoint, making tumor cells reliant on Chk1-mediated G2/M cell cycle arrest for DNA repair. Therefore, Chk1 is a reasonable target for a combination strategy with PARPi in treating BRCA wild type HGSOC. Here we investigated the combination of prexasertib mesylate monohydrate (LY2606368), a Chk1 and Chk2 inhibitor, and a PARP inhibitor, olaparib, in HGSOC cell lines (OVCAR3, OV90, PEO1 and PEO4) using clinically attainable concentrations...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29323270/two-three-strand-intermediates-are-processed-during-rad51-driven-dna-strand-exchange
#4
Kentaro Ito, Yasuto Murayama, Masayuki Takahashi, Hiroshi Iwasaki
During homologous recombination, Rad51 forms a nucleoprotein filament with single-stranded DNA (ssDNA) that undergoes strand exchange with homologous double-stranded DNA (dsDNA). Here, we use real-time analysis to show that strand exchange by fission yeast Rad51 proceeds via two distinct three-strand intermediates, C1 and C2. Both intermediates contain Rad51, but whereas the donor duplex remains intact in C1, the ssDNA strand is intertwined with the complementary strand of the donor duplex in C2. Swi5-Sfr1, an evolutionarily conserved recombination activator, facilitates the C1-C2 transition and subsequent ssDNA release from C2 to complete strand exchange in an ATP-hydrolysis-dependent manner...
January 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29298824/mof-suppresses-replication-stress-and-contribute-to-resolution-of-stalled-replication-forks
#5
Dharmendra Kumar Singh, Raj K Pandita, Mayank Singh, Sharmistha Chakraborty, Shashank Hambarde, Deepti Ramnarain, Vijaya Charaka, Kazi Mokim Ahmed, Clayton R Hunt, Tej K Pandita
The hMOF protein belongs to the MYST family of histone acetyltransferases and plays a critical role in transcription and the DNA damage response. MOF is essential for cell proliferation, however its role during replication and replicative stress is unknown. Here we demonstrate that cells depleted for MOF and under replicative stress induced by cisplatin, hydroxyurea or camptothecin have reduced survival, a higher frequency of S-phase specific chromosome damage and increased R-loop formation. MOF depletion decreased replication fork speed and, when combined with replicative stress, also increased stalled replication forks as well as new origin firing...
January 3, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29295984/rad54-n-terminal-domain-is-a-dna-sensor-that-couples-atp-hydrolysis-with-branch-migration-of-holliday-junctions
#6
Nadish Goyal, Matthew J Rossi, Olga M Mazina, Yong Chi, Robert L Moritz, Bruce E Clurman, Alexander V Mazin
In eukaryotes, RAD54 catalyzes branch migration (BM) of Holliday junctions, a basic process during DNA repair, replication, and recombination. RAD54 also stimulates RAD51 recombinase and has other activities. Here, we investigate the structural determinants for different RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29290471/resolving-the-gordian-knot-srs2-strips-intermediates-formed-during-homologous-recombination
#7
Harshad Ghodke, Jacob S Lewis, Antoine M van Oijen
Cells use a suite of specialized enzymes to repair chromosomal double-strand breaks (DSBs). Two recent studies describe how single-molecule fluorescence imaging techniques are used in the direct visualization of some of the key molecular steps involved. De Tullio et al. and Kaniecki et al. watch individual Srs2 helicase molecules disrupt repair intermediates formed by RPA, Rad51, and Rad52 on DNA during homologous recombination.
December 28, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/29290255/egfr-rad51-fusion-variant-in-lung-adenocarcinoma-and-response-to-erlotinib-a-case-report
#8
You-Cai Zhu, Wen-Xian Wang, Chun-Wei Xu, Zheng-Bo Song, Kai-Qi Du, Gang Chen, Tang-Feng Lv, Yong Song
The most frequent epidermal growth factor receptor (EGFR) mutations of lung cancer include exon 19 in deletion and the exon 21 L858R mutation. And EGFR-tyrosine kinase inhibitor (TKI) as the standard first line treatment show good response to classical/sensitizing EGFR mutations. With the development of detection methods, some uncommon genomic mutation events such as exon 18-25 kinase domain duplications (KDD) and EGFR rearrangements (EGFR-RAD51 or EGFR-PURB) are found. We reported a case of EGFR-RAD51 fusion in non-small-cell lung cancer(NSCLC) and the efficacy of erlotinib to this type fusion of NSCLC patients...
January 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29287594/comprehensive-molecular-biomarker-identification-in-breast-cancer-brain-metastases
#9
Hans-Juergen Schulten, Mohammed Bangash, Sajjad Karim, Ashraf Dallol, Deema Hussein, Adnan Merdad, Fatma K Al-Thoubaity, Jaudah Al-Maghrabi, Awatif Jamal, Fahad Al-Ghamdi, Hani Choudhry, Saleh S Baeesa, Adeel G Chaudhary, Mohammed H Al-Qahtani
BACKGROUND: Breast cancer brain metastases (BCBM) develop in about 20-30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques. METHODS: We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p < 0...
December 29, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/29284495/tumor-treating-fields-ttfields-delay-dna-damage-repair-following-radiation-treatment-of-glioma-cells
#10
Moshe Giladi, Mijal Munster, Rosa S Schneiderman, Tali Voloshin, Yaara Porat, Roni Blat, Katarzyna Zielinska-Chomej, Petra Hååg, Ze'ev Bomzon, Eilon D Kirson, Uri Weinberg, Kristina Viktorsson, Rolf Lewensohn, Yoram Palti
BACKGROUND: Tumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells...
December 29, 2017: Radiation Oncology
https://www.readbyqxmd.com/read/29279302/genetic-evidence-for-roles-of-yeast-mitotic-cyclins-at-single-stranded-gaps-created-by-dna-replication
#11
Laurence Signon
Paused/stalled replication forks are major threats to genome integrity; unraveling the complex pathways that contribute to fork stability/restart is crucial. Experimentally, fork stalling is induced by growth in presence of hydroxyurea (HU), which depletes the pool of deoxynucleoside triphosphates (dNTPs) and slows down replication progression in yeast. Here, I report an epistasis analysis, based on sensitivity to HU, between CLB2, the principal mitotic cyclin gene in S. cerevisiae, and genes involved in fork stability and recombination...
December 26, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29273627/precise-and-efficient-nucleotide-substitution-near-genomic-nick-via-noncanonical-homology-directed-repair
#12
Kazuhiro Nakajima, Yue Zhou, Akiko Tomita, Yoshihiro Hirade, Channabasavaiah B Gurumurthy, Shinichiro Nakada
CRISPR/Cas9, which generates DNA double-strand breaks (DSBs) at target loci, is a powerful tool for editing genomes when codelivered with a donor DNA template. However, DSBs, which are the most deleterious type of DNA damage, often result in unintended nucleotide insertions/deletions (indels) via mutagenic nonhomologous end joining. We developed a strategy for precise gene editing that does not generate DSBs. We show that a combination of single nicks in the target gene and donor plasmid (SNGD) using Cas9D10A nickase promotes efficient nucleotide substitution by gene editing...
December 22, 2017: Genome Research
https://www.readbyqxmd.com/read/29241544/dissociation-of-rad51-presynaptic-complexes-and-heteroduplex-dna-joints-by-tandem-assemblies-of-srs2
#13
Kyle Kaniecki, Luisina De Tullio, Bryan Gibb, Youngho Kwon, Patrick Sung, Eric C Greene
Srs2 is a superfamily 1 (SF1) helicase and antirecombinase that is required for genome integrity. However, the mechanisms that regulate Srs2 remain poorly understood. Here, we visualize Srs2 as it acts upon single-stranded DNA (ssDNA) bound by the Rad51 recombinase. We demonstrate that Srs2 is a processive translocase capable of stripping thousands of Rad51 molecules from ssDNA at a rate of ∼50 monomers/s. We show that Srs2 is recruited to RPA clusters embedded between Rad51 filaments and that multimeric arrays of Srs2 assemble during translocation on ssDNA through a mechanism involving iterative Srs2 loading events at sites cleared of Rad51...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29240261/mitochondrial-dysfunction-rad51-and-ku80-proteolysis-promote-apoptotic-effects-of-dinaciclib-in-bcl-xl-silenced-cells
#14
Daniel R Premkumar, Esther P Jane, Swetha Thambireddy, Philip A Sutera, Jonathon M Cavaleri, Ian F Pollack
In the present study, we investigated the effect of CDK inhibitors (ribociclib, palbociclib, seliciclib, AZD5438 and dinaciclib) on malignant human glioma cells for cell viability, apoptosis, oxidative stress and mitochondrial function using various assays. None of the CDK inhibitors induced cell death at a clinically relevant concentration. However, low nanomolar concentrations of dinaciclib showed higher cytotoxic activity against Bcl-xL silenced cells in a time- and concentration-dependent manner. This effect was not seen with other CDK inhibitors...
December 14, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29233223/a-stretched-conformation-of-dna-with-a-biological-role
#15
Niklas Bosaeus, Anna Reymer, Tamás Beke-Somfai, Tom Brown, Masayuki Takahashi, Pernilla Wittung-Stafshede, Sandra Rocha, Bengt Nordén
We have discovered a well-defined extended conformation of double-stranded DNA, which we call Σ-DNA, using laser-tweezers force-spectroscopy experiments. At a transition force corresponding to free energy change ΔG = 1·57 ± 0·12 kcal (mol base pair)-1 60 or 122 base-pair long synthetic GC-rich sequences, when pulled by the 3'-3' strands, undergo a sharp transition to the 1·52 ± 0·04 times longer Σ-DNA. Intriguingly, the same degree of extension is also found in DNA complexes with recombinase proteins, such as bacterial RecA and eukaryotic Rad51...
January 2017: Quarterly Reviews of Biophysics
https://www.readbyqxmd.com/read/29228610/targeting-polo-like-kinase-1-in-smarcb1-deleted-atypical-teratoid-rhabdoid-tumor
#16
Irina Alimova, Angela M Pierce, Peter Harris, Andrew Donson, Diane K Birks, Eric Prince, Ilango Balakrishnan, Nicholas K Foreman, Marcel Kool, Lindsey Hoffman, Sujatha Venkataraman, Rajeev Vibhakar
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive and malignant pediatric brain tumor. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and essential for mitosis. Overexpression of PLK1 promotes chromosome instability and aneuploidy by overriding the G2-M DNA damage and spindle checkpoints. Recent studies suggest that targeting PLK1 by small molecule inhibitors is a promising approach to tumor therapy. We investigated the effect of PLK1 inhibition in ATRT. Gene expression analysis showed that PLK1 was overexpressed in ATRT patient samples and tumor cell lines...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29220651/replication-fork-reversal-players-and-guardians
#17
REVIEW
Annabel Quinet, Delphine Lemaçon, Alessandro Vindigni
Replication fork reversal is a rapidly emerging and remarkably frequent mechanism of fork stabilization in response to genotoxic insults. Here, we summarize recent findings that uncover key molecular determinants for reversed fork formation and describe how the homologous recombination factors BRCA1, BRCA2, and RAD51 protect these structures from extended nucleolytic degradation.
December 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29217481/dna-damage-and-repair-proteins-in-cellular-response-to-sulfur-mustard-in-iranian-veterans-more-than-two-decades-after-exposure
#18
Shahriar Khateri, Mahdi Balali-Mood, Peter Blain, Faith Williams, Paul Jowsey, Mohammad Reza Soroush, Effat Behravan, Mahmood Sadeghi
Delayed effects of sulfur mustard (SM) exposure on the levels of five important damage/repair proteins were investigated in 40 SM-exposed veterans of Iran-Iraq war and 35 unexposed controls. A major DNA damage biomarker protein - phosphorylated H2AX - along with four DNA repair proteins in cell response to the genome damage MRE11, NBS1, RAD51, and XPA were evaluated in blood lymphocytes from the veterans and controls using western blotting. Mean levels of XPA, MRE11, RAD51 and NBS1 were lower in SM-exposed patients and the decrease in NBS1 was significant...
December 4, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/29216366/lncrna-lnc-ri-regulates-homologous-recombination-repair-of-dna-double-strand-breaks-by-stabilizing-rad51-mrna-as-a-competitive-endogenous-rna
#19
Liping Shen, Qi Wang, Ruixue Liu, Zhongmin Chen, Xueqing Zhang, Pingkun Zhou, Zhidong Wang
DNA double-strand break (DSB) repair is critical for the maintenance of genome stability. The current models of the mechanism of DSB repair are based on studies of DNA repair proteins. Long non-coding RNAs (lncRNAs) have recently emerged as new regulatory molecules, with diverse functions in biological processes. In the present study, we found that expression of the ionizing radiation-inducible lncRNA, lnc-RI, was correlate negatively with micronucleus frequencies in human peripheral blood lymphocytes. Knockdown of lnc-RI significantly increased spontaneous DSBs levels, which was confirmed to be associated with the decreased efficiency of homologous recombination (HR) repair of DSBs...
December 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29215009/the-end-joining-factor-ku-acts-in-the-end-resection-of-double-strand-break-free-arrested-replication-forks
#20
Ana Teixeira-Silva, Anissia Ait Saada, Julien Hardy, Ismail Iraqui, Marina Charlotte Nocente, Karine Fréon, Sarah A E Lambert
Replication requires homologous recombination (HR) to stabilize and restart terminally arrested forks. HR-mediated fork processing requires single stranded DNA (ssDNA) gaps and not necessarily double strand breaks. We used genetic and molecular assays to investigate fork-resection and restart at dysfunctional, unbroken forks in Schizosaccharomyces pombe. Here, we report that fork-resection is a two-step process regulated by the non-homologous end joining factor Ku. An initial resection mediated by MRN-Ctp1 removes Ku from terminally arrested forks, generating ~110 bp sized gaps obligatory for subsequent Exo1-mediated long-range resection and replication restart...
December 7, 2017: Nature Communications
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