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https://www.readbyqxmd.com/read/29851556/mre11-rad50-dependent-activity-of-atm-tel1-at-dna-breaks-and-telomeres-in-the-absence-of-nbs1
#1
Oliver Limbo, Yoshiki Yamada, Paul Russell
The Mre11-Rad50-Nbs1 (MRN) protein complex and ATM/Tel1 kinase protect genome integrity through their functions in DNA double-strand break (DSB) repair, checkpoint signaling, and telomere maintenance. Nbs1 has a conserved C-terminal motif that binds ATM/Tel1, but the full extent and significance of ATM/Tel1 interactions with MRN are unknown. Here, we show that Tel1 overexpression bypasses the requirement for Nbs1 in DNA damage signaling and telomere maintenance. These activities require Mre11-Rad50, which localizes to DSBs and bind Tel1 in the absence of Nbs1...
June 1, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29844578/destabilization-of-linker-histone-h1-2-is-essential-for-atm-activation-and-dna-damage-repair
#2
Zhiming Li, Yinglu Li, Ming Tang, Bin Peng, Xiaopeng Lu, Qiaoyan Yang, Qian Zhu, Tianyun Hou, Meiting Li, Chaohua Liu, Lina Wang, Xingzhi Xu, Ying Zhao, Haiying Wang, Yang Yang, Wei-Guo Zhu
Linker histone H1 is a master regulator of higher order chromatin structure, but its involvement in the DNA damage response and repair is unclear. Here, we report that linker histone H1.2 is an essential regulator of ataxia telangiectasia mutated (ATM) activation. We show that H1.2 protects chromatin from aberrant ATM activation through direct interaction with the ATM HEAT repeat domain and inhibition of MRE11-RAD50-NBS1 (MRN) complex-dependent ATM recruitment. Upon DNA damage, H1.2 undergoes rapid PARP1-dependent chromatin dissociation through poly-ADP-ribosylation (PARylation) of its C terminus and further proteasomal degradation...
May 29, 2018: Cell Research
https://www.readbyqxmd.com/read/29769345/the-major-tegument-protein-of-bovine-herpesvirus-1-vp8-interacts-with-dna-damage-response-proteins-and-induces-apoptosis
#3
Sharmin Afroz, Ravendra Garg, Michel Fodje, Sylvia van Drunen Littel-van den Hurk
VP8, the UL47 gene product in bovine herpes virus-1 (BoHV-1), is a major tegument protein, essential for virus replication in vivo The major DNA damage response protein, ataxia telangiectasia mutated (ATM), phosphorylates Nijmegen breakage syndrome (NBS1) and structural maintenance of chromosome-1 (SMC1) proteins during the DNA damage response. VP8 was found to interact with ATM and NBS1 during transfection and BoHV-1 infection. However, VP8 did not interfere with phosphorylation of ATM in transfected or BoHV-1-infected cells...
May 16, 2018: Journal of Virology
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
#4
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/29686104/interdependent-and-separable-functions-of-caenorhabditis-elegans-mrn-c-complex-members-couple-formation-and-repair-of-meiotic-dsbs
#5
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...
May 8, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29679095/implication-of-the-vrk1-chromatin-kinase-in-the-signaling-responses-to-dna-damage-a-therapeutic-target
#6
REVIEW
Ignacio Campillo-Marcos, Pedro A Lazo
DNA damage causes a local distortion of chromatin that triggers the sequential processes that participate in specific DNA repair mechanisms. This initiation of the repair response requires the involvement of a protein whose activity can be regulated by histones. Kinases are candidates to regulate and coordinate the connection between a locally altered chromatin and the response initiating signals that lead to identification of the type of lesion and the sequential steps required in specific DNA damage responses (DDR)...
July 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29547809/serotype-specific-restriction-of-wild-type-adenoviruses-by-the-cellular-mre11-rad50-nbs1-complex
#7
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/29524880/isoorientin-triggers-apoptosis-of-hepatoblastoma-by-inducing-dna-double-strand-breaks-and-suppressing-homologous-recombination-repair
#8
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
#9
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/29514136/deficiency-in-dna-damage-response-of-enterocytes-accelerates-intestinal-stem-cell-aging-in-drosophila
#10
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
https://www.readbyqxmd.com/read/29458776/methods-to-study-dna-end-resection-ii-biochemical-reconstitution-assays
#11
Cosimo Pinto, Roopesh Anand, Petr Cejka
DNA end resection initiates the largely accurate repair of DNA double-strand breaks (DSBs) by homologous recombination. Specifically, recombination requires the formation of 3' overhangs at DSB sites, which is carried out by nucleases that specifically degrade 5'-terminated DNA. In most cases, DNA end resection is a two-step process, comprising of initial short-range followed by more processive long-range resection. In this chapter, we describe selected assays that reconstitute both the short- and long-range pathways...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29458761/methods-to-study-dna-end-resection-i-recombinant-protein-purification
#12
Roopesh Anand, Cosimo Pinto, Petr Cejka
Accurate repair of DNA double-strand breaks (DSBs) is carried out by homologous recombination. In order to repair DNA breaks by the recombination pathway, the 5'-terminated DNA strand at DSB sites must be first nucleolytically processed to produce 3'-overhang. The process is termed DNA end resection and involves the interplay of several nuclease complexes. DNA end resection commits DSB repair to the recombination pathway including a process termed single-strand annealing, as resected DNA ends are generally nonligatable by the competing nonhomologous end-joining machinery...
2018: Methods in Enzymology
https://www.readbyqxmd.com/read/29433451/nbs1-rs2735383-polymorphism-is-associated-with-an-increased-risk-of-laryngeal-carcinoma
#13
Xinmei Hu, Juan Liao, Huiliu Zhao, Feng Chen, Xuefeng Zhu, Jiangheng Li, Qingqing Nong
BACKGROUND: Nijmegen breakage syndrome 1 (NBS1), as a key protein in the DNA double-strand breaks (DSBs) repair pathway, plays an important role in maintaining genomic stability. Although single nucleotide polymorphisms (SNPs) in NBS1 have frequently been studied in multiple cancers, the relationships of two functional NBS1 polymorphisms (rs2735383 and rs1805794) with laryngeal carcinoma are yet unclear. Therefore, in the present study, we performed a case-control study including 342 cases and 345 controls to analyze the associations between two polymorphisms of NBS1 and the risk of laryngeal carcinoma...
February 12, 2018: BMC Cancer
https://www.readbyqxmd.com/read/29432179/parp-1-dependent-recruitment-of-cold-inducible-rna-binding-protein-promotes-double-strand-break-repair-and-genome-stability
#14
Jung-Kuei Chen, Wen-Ling Lin, Zhang Chen, Hung-Wen Liu
Maintenance of genome integrity is critical for both faithful propagation of genetic information and prevention of mutagenesis induced by various DNA damage events. Here we report cold-inducible RNA-binding protein (CIRBP) as a newly identified key regulator in DNA double-strand break (DSB) repair. On DNA damage, CIRBP temporarily accumulates at the damaged regions and is poly(ADP ribosyl)ated by poly(ADP ribose) polymerase-1 (PARP-1). Its dissociation from the sites of damage may depend on its phosphorylation status as mediated by phosphatidylinositol 3-kinase-related kinases...
February 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29416357/a-non-synonymous-polymorphism-in-nbs1-is-associated-with-progression-from-chronic-hepatitis-b-virus-infection-to-hepatocellular-carcinoma-in-a-chinese-population
#15
Ya'nan Zhen, Ruixue Xiao, Xing Chen, Changjin Yuan, Yanlai Sun, Jie Li
Purpose: Nijmegen breakage syndrome 1 (NBS1) has a vital role in DNA double-strand break (DSB) repair, functioning as a sensor to identify and repair DNA damage and maintaining genomic stability by participating in the intra-S-phase checkpoint. Polymorphisms of NBS1 have been investigated in multiple cancers with variable results. To our best knowledge, no previous study has focused on the association between NBS1 single-nucleotide polymorphisms (SNPs) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC)...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29396424/inactivation-of-ribosomal-protein-s27-like-confers-radiosensitivity-via-the-mdm2-p53-and-mdm2-mrn-atm-axes
#16
Yongchao Zhao, Mingjia Tan, Xia Liu, Xiufang Xiong, Yi Sun
RPS27L (ribosomal protein S27-like) is an evolutionarily conserved ribosomal protein and a direct p53 target. We recently reported that Rps27l disruption triggers ribosomal stress to induce p53, causing postnatal death, which can be rescued by Trp53 +/- . Whether and how Rps27l modulates radiosensitivity is unknown. Here we report that Rps27l -/- ; Trp53 +/- mice are extremely sensitive to radiation due to reduced proliferation and massive induction of apoptosis in radiation-sensitive organs. Mechanistically, the radiation sensitivity is mediated by two signaling pathways: (1) activated p53 pathway due to imbalanced Mdm2/Mdm4 levels and reduced E3 ligase activity; and (2) reduced DNA damage response due to reduced MRN/Atm signal as a result of elevated Mdm2 binding of Nbs1 to inhibit Nbs1-Atm binding and subsequent Atm activation...
February 2, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29368209/breast-cancer-risk-associated-with-genes-encoding-dna-repair-mrn-complex-a-study-from-punjab-pakistan
#17
Rabbia Tariq Khan, Ayesha Siddique, Naeem Shahid, Samina Khokher, Warda Fatima
BACKGROUND: Variants of DNA repair genes are extensively reported to cause genetic instability and increase the risk of breast cancer. In combination with NBS1, MRE11 and RAD50 constitute an MRN (MRE11-RAD50-NBS1) complex that repairs DNA damage. However, certain genetic alterations in MRE11 and RAD50 produce abnormal protein that affects the repairing process and may result in malignancy. We aimed to investigate the association of MRE11 and RAD50 polymorphisms with breast risk in the female population of Punjab, Pakistan...
January 24, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29361783/localization-microscopy-analyses-of-mre11-clusters-in-3d-conserved-cell-nuclei-of-different-cell-lines
#18
Marion Eryilmaz, Eberhard Schmitt, Matthias Krufczik, Franziska Theda, Jin-Ho Lee, Christoph Cremer, Felix Bestvater, Wladimir Schaufler, Michael Hausmann, Georg Hildenbrand
In radiation biophysics, it is a subject of nowadays research to investigate DNA strand break repair in detail after damage induction by ionizing radiation. It is a subject of debate as to what makes up the cell's decision to use a certain repair pathway and how the repair machinery recruited in repair foci is spatially and temporarily organized. Single-molecule localization microscopy (SMLM) allows super-resolution analysis by precise localization of single fluorescent molecule tags, resulting in nuclear structure analysis with a spatial resolution in the 10 nm regime...
January 22, 2018: Cancers
https://www.readbyqxmd.com/read/29322791/targeting-rad50-increases-sensitivity-to-radiotherapy-in-colorectal-cancer-cells
#19
C Chen, Y Wang, J F Mei, S S Li, H X Xu, H P Xiong, X H Wang, X He
Radiotherapy resistance remains the major factor limiting the radiotherapy efficacy in colorectal cancer. The Mre11-RAD50-Nbs1 (MRN) complex is known to play a critical role in the DNA double strand breaks (DSBs) repair pathways and thus facilitates radioresistance. Targeting MRN function can sensitize cancer cells to irradiation in some malignancies. In this study, we stably knocked down RAD50 protein in colorectal cancer (CRC) cell lines, HCT116 and DLD1, and evaluated their response to irradiation as well as the DSB repair dynamics...
2018: Neoplasma
https://www.readbyqxmd.com/read/29317520/atm-directs-dna-damage-responses-and-proteostasis-via-genetically-separable-pathways
#20
Ji-Hoon Lee, Michael R Mand, Chung-Hsuan Kao, Yi Zhou, Seung W Ryu, Alicia L Richards, Joshua J Coon, Tanya T Paull
The protein kinase ATM is a master regulator of the DNA damage response but also responds directly to oxidative stress. Loss of ATM causes ataxia telangiectasia, a neurodegenerative disorder with pleiotropic symptoms that include cerebellar dysfunction, cancer, diabetes, and premature aging. We genetically separated the activation of ATM by DNA damage from that by oxidative stress using separation-of-function mutations. We found that deficient activation of ATM by the Mre11-Rad50-Nbs1 complex and DNA double-strand breaks resulted in loss of cell viability, checkpoint activation, and DNA end resection in response to DNA damage...
January 9, 2018: Science Signaling
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