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https://www.readbyqxmd.com/read/28335590/roles-of-budding-yeast-hrr25-in-recombination-and-sporulation
#1
Min-Su Lee, Jeong Hwan Joo, Keunpil Kim
Hrr25, a casein kinase 1 δ/ε homolog in budding yeast, is essential to set up mono-orientation of sister kinetochores during meiosis. Hrr25 kinase activity coordinates sister chromatid cohesion via cohesin phosphorylation. Here, we investigated the prophase roles of Hrr25 using the auxin-inducible degron system and by ectopic expression of Hrr25 during yeast meiosis. Hrr25 mediates nuclear division in meiosis I but does not affect DNA replication. We also found that initiation of meiotic double-strand breaks as well as joint molecule formation were normal in HRR25-deficient cells...
March 24, 2017: Journal of Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28334931/rgf1p-rho1p-gef-is-required-for-double-strand-break-repair-in-fission-yeast
#2
Elvira Manjón, Tomás Edreira, Sofía Muñoz, Yolanda Sánchez
Rho GTPases are conserved molecules that control cytoskeletal dynamics. These functions are expedited by Rho GEFs that stimulate the release of GDP to enable GTP binding, thereby allowing Rho proteins to initiate intracellular signaling. How Rho GEFs and Rho GTPases protect cells from DNA damage is unknown. Here, we explore the extreme sensitivity of a deletion mutation in the Rho1p exchange factor Rgf1p to the DNA break/inducing antibiotic phleomycin (Phl). The Rgf1p mutant cells are defective in reentry into the cell cycle following the induction of severe DNA damage...
March 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334891/rad51-interconnects-between-dna-replication-dna-repair-and-immunity
#3
Souparno Bhattacharya, Kalayarasan Srinivasan, Salim Abdisalaam, Fengtao Su, Prithvi Raj, Igor Dozmorov, Ritu Mishra, Edward K Wakeland, Subroto Ghose, Shibani Mukherjee, Aroumougame Asaithamby
RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. In the absence of RAD51, the unprotected newly replicated genome is degraded by the exonuclease activity of MRE11, and the fragmented nascent DNA accumulates in the cytosol, initiating an innate immune response...
February 21, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334836/trypanosoma-brucei-rap1-maintains-telomere-and-subtelomere-integrity-by-suppressing-terra-and-telomeric-rna-dna-hybrids
#4
Vishal Nanavaty, Ranjodh Sandhu, Sanaa E Jehi, Unnati M Pandya, Bibo Li
Trypanosoma brucei causes human African trypanosomiasis and regularly switches its major surface antigen, VSG, thereby evading the host's immune response. VSGs are monoallelically expressed from subtelomeric expression sites (ESs), and VSG switching exploits subtelomere plasticity. However, subtelomere integrity is essential for T. brucei viability. The telomeric transcript, TERRA, was detected in T. brucei previously. We now show that the active ES-adjacent telomere is transcribed. We find that TbRAP1, a telomere protein essential for VSG silencing, suppresses VSG gene conversion-mediated switching...
March 16, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28334174/dna-damage-response-in-hematopoietic-stem-cells-an-evolutionary-trade-off-between-blood-regeneration-and-leukemia-suppression
#5
Shahar Biechonski, Muhammad Yassin, Michael Milyavsky
Self-renewing and multipotent hematopoietic stem cells (HSCs) maintain lifelong hematopoiesis. Their enormous regenerative potential coupled with lifetime persistence in the body, in contrast with the Progenitors, demand tight control of HSCs genome stability. Indeed, failure to accurately repair DNA damage in HSCs is associated with bone marrow failure and accelerated leukemogenesis. Recent observations exposed remarkable differences in several DNA-damage response (DDR) aspects between HSCs and Progenitors, especially in their DNA-repair capacities and susceptibility to apoptosis...
March 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28334093/association-between-mirna-binding-site-polymorphisms-in-double-strand-break-repair-genes-and-risk-of-recurrence-in-patients-with-squamous-cell-carcinomas-of-the-nonoropharynx
#6
Lijun Zhu, Erich M Sturgis, Zhongming Lu, Hua Zhang, Peng Wei, Qingyi Wei, Guojun Li
Genetic polymorphisms at miRNA-binding sites may affect miRNA-mediated gene regulation. Thus, miRNA-binding site polymorphisms in double-strand break (DSB) repair genes may affect DNA repair capacity, which in turn could affect cancer prognosis. To determine whether miRNA-binding site polymorphisms in DSB repair genes are associated with the risk of recurrence of squamous cell carcinoma of the nonoropharynx (SCCNOP), we used a log-rank test and multivariable Cox models to evaluate the associations between miRNA-binding site polymorphisms in DSB repair genes and SCCNOP recurrence...
February 18, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28333135/bre-modulates-granulosa-cell-death-to-affect-ovarian-follicle-development-and-atresia-in-the-mouse
#7
Cheung Kwan Yeung, Guang Wang, Yao Yao, Jianxin Liang, Cheuk Yiu Tenny Chung, Manli Chuai, Kenneth Ka Ho Lee, Xuesong Yang
The BRE (brain and reproductive expression) gene, highly expressed in nervous and reproductive system organs, plays an important role in modulating DNA damage repair under stress response and pathological conditions. Folliculogenesis, a process that ovarian follicle develops into maturation, is closely associated with the interaction between somatic granulosa cell and oocyte. However, the regulatory role of BRE in follicular development remains undetermined. In this context, we found that BRE is normally expressed in the oocytes and granulosa cells from the primordial follicle stage...
March 23, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28331416/dna-pk-inhibition-by-nu7441-enhances-chemosensitivity-to-topoisomerase-inhibitor-in-non-small-cell-lung-carcinoma-cells-by-blocking-dna-damage-repair
#8
Masaaki Yanai, Haruhiko Makino, Bingqiong Ping, Kenichi Takeda, Natsumi Tanaka, Tomohiro Sakamoto, Kosuke Yamaguchi, Masahiro Kodani, Akira Yamasaki, Tadashi Igishi, Eiji Shimizu
BACKGROUND: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells...
March 2017: Yonago Acta Medica
https://www.readbyqxmd.com/read/28331197/efficient-generation-of-dirnas-requires-components-in-the-posttranscriptional-gene-silencing-pathway
#9
Daisuke Miki, Peiying Zhu, Wencan Zhang, Yanfei Mao, Zhengyan Feng, Huan Huang, Hui Zhang, Yanqiang Li, Renyi Liu, Huiming Zhang, Yijun Qi, Jian-Kang Zhu
It has been reported that double-stranded break (DSB)-induced small RNAs (diRNAs) are generated via the RNA-directed DNA methylation pathway and function in DSB repair in Arabidposis. However, important questions remain regarding the biogenesis and function of diRNAs. Here, we used CRISPR/Cas9- or TALEN-triggered DSBs to characterize diRNAs in Arabidopsis and rice. We found that 21-nt diRNAs were generated from a 35S promoter::GU-US reporter transgene targeted by CRISPR/Cas9. Unexpectedly, Pol II transcription of the transgene was required for efficient diRNA production and the level of diRNA accumulation correlated with the expression level of the transgene...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28329681/sirt6-promotes-dna-end-joining-in-ipscs-derived-from-old-mice
#10
Wen Chen, Nana Liu, Hongxia Zhang, Haiping Zhang, Jing Qiao, Wenwen Jia, Songcheng Zhu, Zhiyong Mao, Jiuhong Kang
Induced pluripotent stem cells (iPSCs) have great potential for treating age-related diseases, but the genome integrity of iPSCs is critically important. Here, we demonstrate that non-homologous end joining (NHEJ), rather than homologous recombination (HR), is less efficient in iPSCs from old mice than young mice. We further find that Sirt6 is downregulated in iPSCs from old mice. Sirt6 directly binds to Ku80 and facilitates the Ku80/DNA-PKcs interaction, thus promoting DNA-PKcs phosphorylation at residue S2056, leading to efficient NHEJ...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28327192/dna-double-strand-breaks-in-human-induced-pluripotent-stem-cell-reprogramming-and-long-term-in-vitro-culturing
#11
Pavel Simara, Lenka Tesarova, Daniela Rehakova, Pavel Matula, Stanislav Stejskal, Ales Hampl, Irena Koutna
BACKGROUND: Human induced pluripotent stem cells (hiPSCs) play roles in both disease modelling and regenerative medicine. It is critical that the genomic integrity of the cells remains intact and that the DNA repair systems are fully functional. In this article, we focused on the detection of DNA double-strand breaks (DSBs) by phosphorylated histone H2AX (known as γH2AX) and p53-binding protein 1 (53BP1) in three distinct lines of hiPSCs, their source cells, and one line of human embryonic stem cells (hESCs)...
March 21, 2017: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/28325877/dual-utility-nls-drives-rnf169-dependent-dna-damage-responses
#12
Liwei An, Yiyang Jiang, Howin H W Ng, Ellen P S Man, Jie Chen, Ui-Soon Khoo, Qingguo Gong, Michael S Y Huen
Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives cell cycle checkpoint activation but is counterproductive to high-fidelity DNA repair. ring finger protein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. We report here that this attribute is accomplished, in part, by a predicted nuclear localization signal (NLS) that not only shuttles RNF169 into the nucleus but also promotes its stability by mediating a direct interaction with the ubiquitin-specific protease USP7...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28325870/crispr-cas9-guided-oncogenic-chromosomal-translocations-with-conditional-fusion-protein-expression-in-human-mesenchymal-cells
#13
Fabio Vanoli, Mark Tomishima, Weiran Feng, Khadija Lamribet, Loelia Babin, Erika Brunet, Maria Jasin
Gene editing techniques have been extensively used to attempt to model recurrent genomic rearrangements found in tumor cells. These methods involve the induction of double-strand breaks at endogenous loci followed by the identification of breakpoint junctions within a population, which typically arise by nonhomologous end joining. The low frequency of these events, however, has hindered the cloning of cells with the desired rearrangement before oncogenic transformation. Here we present a strategy combining CRISPR-Cas9 technology and homology-directed repair to allow for the selection of human mesenchymal stem cells harboring the oncogenic translocation EWSR1-WT1 found in the aggressive desmoplastic small round cell tumor...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28325102/building-up-and-breaking-down-mechanisms-controlling-recombination-during-replication
#14
Dana Branzei, Barnabas Szakal
The complete and faithful duplication of the genome is an essential prerequisite for proliferating cells to maintain genome integrity. This objective is greatly challenged by DNA damage encountered during replication, which causes fork stalling and in certain cases, fork breakage. DNA damage tolerance (DDT) pathways mitigate the effects on fork stability induced by replication fork stalling by mediating damage-bypass and replication fork restart. These DDT mechanisms, largely relying on homologous recombination (HR) and specialized polymerases, can however contribute to genome rearrangements and mutagenesis...
March 22, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28324505/probing-the-telomere-damage-response
#15
Rekha Rai, Sandy Chang
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28324504/cytogenetic-analysis-of-telomere-dysfunction
#16
Rekha Rai, Asha S Multani, Sandy Chang
Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by the removal of telomere-binding proteins are recognized as double-stranded breaks (DSBs). Repair of DSBs is crucial for the maintenance of genome stability. In mammals, DSBs are repaired by either error-prone nonhomologous end joining (NHEJ) or error-free homologous recombination (HR) and can be visualized as chromosomal fusions.
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28323334/the-emerging-role-of-homologous-recombination-repair-and-parp-inhibitors-in-genitourinary-malignancies
#17
REVIEW
Kalen J Rimar, Phuoc T Tran, Richard S Matulewicz, Maha Hussain, Joshua J Meeks
As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment...
March 21, 2017: Cancer
https://www.readbyqxmd.com/read/28320884/replication-restart-in-bacteria
#18
Bénédicte Michel, Steven J Sandler
In bacteria replication forks assembled at a replication origin travel to the terminus, often a few megabases away. They may encounter obstacles that trigger replisome disassembly, rendering replication restart from abandoned forks crucial for cell viability. During the past 25 years the genes that encode replication restart proteins have been identified and genetically characterized. In parallel, the enzymes were purified and analyzed in vitro, where they can catalyze replication initiation in a sequence-independent manner from fork-like DNA structures...
March 20, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28317934/dek-is-required-for-homologous-recombination-repair-of-dna-breaks
#19
Eric A Smith, Boris Gole, Nicholas A Willis, Rebeca Soria, Linda M Starnes, Eric F Krumpelbeck, Anil G Jegga, Abdullah M Ali, Haihong Guo, Amom R Meetei, Paul R Andreassen, Ferdinand Kappes, Lisa M Privette Vinnedge, Jeremy A Daniel, Ralph Scully, Lisa Wiesmüller, Susanne I Wells
DEK is a highly conserved chromatin-bound protein whose upregulation across cancer types correlates with genotoxic therapy resistance. Loss of DEK induces genome instability and sensitizes cells to DNA double strand breaks (DSBs), suggesting defects in DNA repair. While these DEK-deficiency phenotypes were thought to arise from a moderate attenuation of non-homologous end joining (NHEJ) repair, the role of DEK in DNA repair remains incompletely understood. We present new evidence demonstrating the observed decrease in NHEJ is insufficient to impact immunoglobulin class switching in DEK knockout mice...
March 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28317242/chemical-screening-identifies-rock-as-a-target-for-recovering-mitochondrial-function-in-hutchinson-gilford-progeria-syndrome
#20
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Hyo Jei Claudia Choi, Chul Won Jung, Gyu Ree Kim, Young-Sam Lee, Sang Chul Park
Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent...
March 19, 2017: Aging Cell
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