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https://www.readbyqxmd.com/read/29775409/transactivation-domain-of-p53-regulates-dna-repair-and-integrity-in-human-ips-cells
#1
Ramaswamy Kannappan, Saidulu Mattapally, Pooja A Wagle, Jianyi Zhang
The role of p53 transactivation domain (p53-TAD), a multifunctional and dynamic domain, on DNA repair and retaining DNA integrity in human iPS cells has never been studied. p53-TAD was knocked out in iPS cells using CRISPR/Cas9 and was confirmed by DNA sequencing. p53-TAD KO cells were characterized by: accelerated proliferation, decreased population doubling time, and unaltered Bcl2, BBC3, IGF1R, Bax and altered Mdm2, p21, and PIDD transcripts expression. In p53-TAD KO cells p53 regulated DNA repair proteins XPA, DNA polH and DDB2 expression were found to be reduced compared to p53-WT cells...
May 18, 2018: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29741662/physical-and-functional-interplay-between-pcna-dna-clamp-and-mre11-rad50-complex-from-the-archaeon-pyrococcus-furiosus
#2
Gaëlle Hogrel, Yang Lu, Sébastien Laurent, Etienne Henry, Clarisse Etienne, Duy Khanh Phung, Rémi Dulermo, Audrey Bossé, Pierre-François Pluchon, Béatrice Clouet-d'Orval, Didier Flament
Several archaeal species prevalent in extreme environments are particularly exposed to factors likely to cause DNA damages. These include hyperthermophilic archaea (HA), living at temperatures >70°C, which arguably have efficient strategies and robust genome guardians to repair DNA damage threatening their genome integrity. In contrast to Eukarya and other archaea, homologous recombination appears to be a vital pathway in HA, and the Mre11-Rad50 complex exerts a broad influence on the initiation of this DNA damage response process...
May 8, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29739811/tel1-atm-prevents-degradation-of-replication-forks-that-reverse-after-topoisomerase-poisoning
#3
Luca Menin, Sebastian Ursich, Camilla Trovesi, Ralph Zellweger, Massimo Lopes, Maria Pia Longhese, Michela Clerici
In both yeast and mammals, the topoisomerase poison camptothecin (CPT) induces fork reversal, which has been proposed to stabilize replication forks, thus providing time for the repair of CPT-induced lesions and supporting replication restart. We show that Tel1, the Saccharomyces cerevisiae orthologue of human ATM kinase, stabilizes CPT-induced reversed forks by counteracting their nucleolytic degradation by the MRX complex. Tel1-lacking cells are hypersensitive to CPT specifically and show less reversed forks in the presence of CPT The lack of Mre11 nuclease activity restores wild-type levels of reversed forks in CPT-treated tel1 Δ cells without affecting fork reversal in wild-type cells...
May 8, 2018: EMBO Reports
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/29709199/the-mre11-rad50-nbs1-complex-conducts-the-orchestration-of-damage-signaling-and-outcomes-to-stress-in-dna-replication-and-repair
#5
Aleem Syed, John A Tainer
Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette-ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11-RAD50-NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection...
April 25, 2018: Annual Review of Biochemistry
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/29703825/-samhd1-mutations-disrupt-replication-fork-progression-to-induce-ifn
#7
(no author information available yet)
SAMHD1 activates MRE11 exonuclease activity to prevent release of ssDNA from stalled replication forks.
April 27, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29695495/multiple-arginine-residues-are-methylated-in-drosophila-mre11-and-required-for-survival-following-ionizing-radiation
#8
Qing Yuan, Ran Tian, Haiying Zhao, Lijuan Li, Xiaolin Bi
Mre11 is a key player for DNA double strand break repair. Previous studies have shown that mammalian Mre11 is methylated at multiple arginines in its C-terminal Glycine-Arginine-Rich motif (GAR) by protein arginine methyltransferase PRMT1. Here, we found that the Drosophila Mre11 is methylated at arginines 559, 563, 565, and 569 in the GAR motif by DART1, the Drosophila homolog of PRMT1. Mre11 interacts with DART1 in S2 cells, and this interaction does not require the GAR motif. Arginines methylated Mre11 localizes exclusively in the nucleus as soluble nuclear protein or chromatin-binding protein...
April 25, 2018: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29686104/interdependent-and-separable-functions-of-caenorhabditis-elegans-mrn-c-complex-members-couple-formation-and-repair-of-meiotic-dsbs
#9
Chloe Girard, Baptiste Roelens, Karl A Zawadzki, Anne M Villeneuve
Faithful inheritance of genetic information through sexual reproduction relies on the formation of crossovers between homologous chromosomes during meiosis, which, in turn, relies on the formation and repair of numerous double-strand breaks (DSBs). As DSBs pose a potential threat to the genome, mechanisms that ensure timely and error-free DSB repair are crucial for successful meiosis. Here, we identify NBS-1, the Caenorhabditis elegans ortholog of the NBS1 (mutated in Nijmegen Breakage Syndrome) subunit of the conserved MRE11-RAD50-NBS1/Xrs2 (MRN) complex, as a key mediator of DSB repair via homologous recombination (HR) during meiosis...
April 23, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29678143/genetic-variants-in-atm-h2afx-and-mre11-genes-and-susceptibility-to-breast-cancer-in-the-polish-population
#10
Marta Podralska, Iwona Ziółkowska-Suchanek, Magdalena Żurawek, Agnieszka Dzikiewicz-Krawczyk, Ryszard Słomski, Jerzy Nowak, Agnieszka Stembalska, Karolina Pesz, Maria Mosor
BACKGROUND: DNA damage repair is a complex process, which can trigger the development of cancer if disturbed. In this study, we hypothesize a role of variants in the ATM, H2AFX and MRE11 genes in determining breast cancer (BC) susceptibility. METHODS: We examined the whole sequence of the ATM kinase domain and estimated the frequency of founder mutations in the ATM gene (c.5932G > T, c.6095G > A, and c.7630-2A > C) and single nucleotide polymorphisms (SNPs) in H2AFX (rs643788, rs8551, rs7759, and rs2509049) and MRE11 (rs1061956 and rs2155209) among 315 breast cancer patients and 515 controls...
April 20, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29670289/samhd1-acts-at-stalled-replication-forks-to-prevent-interferon-induction
#11
Flavie Coquel, Maria-Joao Silva, Hervé Técher, Karina Zadorozhny, Sushma Sharma, Jadwiga Nieminuszczy, Clément Mettling, Elodie Dardillac, Antoine Barthe, Anne-Lyne Schmitz, Alexy Promonet, Alexandra Cribier, Amélie Sarrazin, Wojciech Niedzwiedz, Bernard Lopez, Vincenzo Costanzo, Lumir Krejci, Andrei Chabes, Monsef Benkirane, Yea-Lih Lin, Philippe Pasero
SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR-CHK1 checkpoint and allows the forks to restart replication...
April 18, 2018: Nature
https://www.readbyqxmd.com/read/29651020/gfi1-facilitates-efficient-dna-repair-by-regulating-prmt1-dependent-methylation-of-mre11-and-53bp1
#12
Charles Vadnais, Riyan Chen, Jennifer Fraszczak, Zhenbao Yu, Jonathan Boulais, Jordan Pinder, Daria Frank, Cyrus Khandanpour, Josée Hébert, Graham Dellaire, Jean-François Côté, Stéphane Richard, Alexandre Orthwein, Elliot Drobetsky, Tarik Möröy
GFI1 is a transcriptional regulator expressed in lymphoid cells, and an "oncorequisite" factor required for development and maintenance of T-lymphoid leukemia. GFI1 deletion causes hypersensitivity to ionizing radiation, for which the molecular mechanism remains unknown. Here, we demonstrate that GFI1 is required in T cells for the regulation of key DNA damage signaling and repair proteins. Specifically, GFI1 interacts with the arginine methyltransferase PRMT1 and its substrates MRE11 and 53BP1. We demonstrate that GFI1 enables PRMT1 to bind and methylate MRE11 and 53BP1, which is necessary for their function in the DNA damage response...
April 12, 2018: Nature Communications
https://www.readbyqxmd.com/read/29564828/genes-proteins-and-biological-pathways-preventing-chromothripsis
#13
Martin Poot
The highly complex structural genome variations chromothripsis, chromoanasynthesis, and chromoplexy are subsumed under the term chromoanagenesis, which means chromosome rebirth. Precipitated by numerous DNA double-strand breaks, they differ in number of and distances between breakpoints, associated copy number variations, order and orientation of segments, and flanking sequences at joining points. Results from patients with the autosomal dominant cancer susceptibility disorder Li-Fraumeni syndrome implicated somatic TP53 mutations in chromothripsis...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29547809/serotype-specific-restriction-of-wild-type-adenoviruses-by-the-cellular-mre11-rad50-nbs1-complex
#14
Neha J Pancholi, Matthew D Weitzman
During viral replication in the nucleus, the DNA genomes of adenoviruses are accessible to cellular DNA-binding proteins. Human adenovirus type 5 (Ad5) targets the cellular Mre11-Rad50-Nbs1 complex (MRN) to evade detection by the DNA damage response (DDR). Ad5 mutants that cannot target MRN have reduced viral propagation. Previous studies showed that diverse adenovirus serotypes interact differently with MRN. While these studies revealed diverse MRN interactions among serotypes, it remains unclear how these differences influence viral replication...
May 2018: Virology
https://www.readbyqxmd.com/read/29532862/high-glucose-induces-the-proliferation-of-prostatic-cells-via-downregulating-mre11
#15
Chunwei Ye, Yi Cai, Qian Cai, Shunhui Yuan, Fan Huang, Xiaofang Yang, Shuchen He, Zhuoheng Li, Yanwen Wang, Delin Yang, Zhipeng Li
The aim of the present study was to investigate the candidate genes and pathways associated with benign prostatic hyperplasia (BPH) and diabetes. In vitro experiments were performed using normal prostatic epithelial RWPE‑1 and HPr‑1 cells. The cell lines were treated with a high‑glucose solution and MTS and bromodeoxyuridine assays were used to assess cell viability. Transcriptome sequencing was used to screen the candidate genes. The expression of candidate genes was further verified by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting...
June 2018: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29524880/isoorientin-triggers-apoptosis-of-hepatoblastoma-by-inducing-dna-double-strand-breaks-and-suppressing-homologous-recombination-repair
#16
Dehong Huang, Lei Jin, Zhengkang Li, Ji Wu, Ni Zhang, Dianrong Zhou, Xiaorong Ni, Tieying Hou
Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo...
May 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29523790/mrn-complex-dependent-recruitment-of-ubiquitylated-blm-helicase-to-dsbs-negatively-regulates-dna-repair-pathways
#17
Vivek Tripathi, Himanshi Agarwal, Swati Priya, Harish Batra, Priyanka Modi, Monica Pandey, Dhurjhoti Saha, Sathees C Raghavan, Sagar Sengupta
Mutations in BLM in Bloom Syndrome patients predispose them to multiple types of cancers. Here we report that BLM is recruited in a biphasic manner to annotated DSBs. BLM recruitment is dependent on the presence of NBS1, MRE11 and ATM. While ATM activity is essential for BLM recruitment in early phase, it is dispensable in late phase when MRE11 exonuclease activity and RNF8-mediated ubiquitylation of BLM are the key determinants. Interaction between polyubiquitylated BLM and NBS1 is essential for the helicase to be retained at the DSBs...
March 9, 2018: Nature Communications
https://www.readbyqxmd.com/read/29523233/targeting-allostery-with-avatars-to-design-inhibitors-assessed-by-cell-activity-dissecting-mre11-endo-and-exonuclease-activities
#18
Davide Moiani, Daryl A Ronato, Chris A Brosey, Andrew S Arvai, Aleem Syed, Jean-Yves Masson, Elena Petricci, John A Tainer
For inhibitor design, as in most research, the best system is question dependent. We suggest structurally defined allostery to design specific inhibitors that target regions beyond active sites. We choose systems allowing efficient quality structures with conformational changes as optimal for structure-based design to optimize inhibitors. We maintain that evolutionarily related targets logically provide molecular avatars, where this Sanskrit term for descent includes ideas of functional relationships and of being a physical embodiment of the target's essential features without requiring high sequence identity...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29514732/erratum
#19
Enrico Mini, Ida Landini, Laura Lucarini, Andrea Lapucci, Cristina Napoli, Gabriele Perrone, Renato Tassi, Emanuela Masini, Flavio Moroni, Stefania Nobili
The poly(ADP-ribose) polymerase (PARP) enzymes play a key role in the regulation of cellular processes (e.g., DNA damage repair, genomic stability). It has been shown that PARP inhibitors (PARPIs) are selectively cytotoxic against cells having dysfunctions in genes involved in DNA repair mechanisms (synthetic lethality). Drug-induced PARP inhibition potentiates the activity of anticancer drugs such as 5-fluorouracil in enhancing DNA damage, whose repair involves PARP-1 activity. The aim of this study was to evaluate the inhibitory effects of a novel PARPI, HYDAMTIQ, on growth in human tumor cell lines characterized by different features with regard to DNA damage response pathways (BRCA mutational status, microsatellite status, and ATM expression level) and degree of sensitivity/resistance to 5-fluorouracil...
March 5, 2018: Oncology Research
https://www.readbyqxmd.com/read/29514136/deficiency-in-dna-damage-response-of-enterocytes-accelerates-intestinal-stem-cell-aging-in-drosophila
#20
Joung-Sun Park, Ho-Jun Jeon, Jung-Hoon Pyo, Young-Shin Kim, Mi-Ae Yoo
Stem cell dysfunction is closely linked to tissue and organismal aging and age-related diseases, and heavily influenced by the niche cells' environment. The DNA damage response (DDR) is a key pathway for tissue degeneration and organismal aging; however, the precise protective role of DDR in stem cell/niche aging is unclear. The Drosophila midgut is an excellent model to study the biology of stem cell/niche aging because of its easy genetic manipulation and its short lifespan. Here, we showed that deficiency of DDR in Drosophila enterocytes (ECs) accelerates intestinal stem cell (ISC) aging...
March 7, 2018: Aging
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