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Hacer E GursesCila, Muradiye Acar, Furkan B Barut, Mehmet Gunduz, Reidar Grenman, Esra Gunduz
PURPOSE: Recent studies have shown that cancer stem cells are resistant to chemotherapy. The aim of this study was to compare RIF1 gene expression in head and neck, pancreatic cancer and glioma cell lines and the cancer stem cells isolated from these cell lines. METHODS: UT-SCC-74 from Turku University and UT-SCC-74B primary tumor metastasis and neck cancer cell lines, YKG-1 glioma cancer cell line from RIKEN, pancreatic cancer cell lines and ASPC-1 cells from ATCC were grown in cell culture...
December 1, 2016: Clinical and Investigative Medicine. Médecine Clinique et Experimentale
Masahiro Takikawa, Yusuke Tarumoto, Fuyuki Ishikawa
The CST complex is a phylogenetically conserved protein complex consisting of CTC1/Cdc13, Stn1 and Ten1 that protects telomeres on linear chromosomes. Deletion of the fission yeast homologs stn1 and ten1 results in complete telomere loss; however, the precise function of Stn1 is still largely unknown. Here, we have isolated a high-temperature sensitive stn1 allele (termed stn1-1). stn1-1 cells abruptly lost telomeric sequence almost completely at the restrictive temperature. The loss of chromosomal DNA happened without gradual telomere shortening, and extended to 30 kb from the ends of chromosomes...
December 1, 2016: Nucleic Acids Research
Abid R Mattoo, Raj K Pandita, Sharmistha Chakraborty, Vijaya Charaka, Kalpana Mujoo, Clayton R Hunt, Tej K Pandita
Myeloid cell leukemia-1 : MCL-1) is a pro-survival BCL-2 protein family member highly expressed in hematopoietic stem cells (HSCs) and regulated by growth factor signals that manifest anti-apoptotic activity. Here we report that depletion of MCL-1, but not its isoform MCL1S, increases genomic instability and cell sensitivity to ionizing radiation (IR) induced death. MCL-1 association with genomic DNA increased post-irradiation and it co-localized with 53BP1 in foci. Post-irradiation, MCL-1 depleted cells exhibited decreased γ-H2AX foci, decreased phosphorylation of ATR and higher levels of residual 53BP1 and RIF1 foci, suggesting DNA DSB repair by homologous recombination (HR) was compromised...
November 7, 2016: Molecular and Cellular Biology
Maksym Shyian, Stefano Mattarocci, Benjamin Albert, Lukas Hafner, Aleksandra Lezaja, Michael Costanzo, Charlie Boone, David Shore
The Rif1 protein is a negative regulator of DNA replication initiation in eukaryotes. Here we show that budding yeast Rif1 inhibits DNA replication initiation at the rDNA locus. Absence of Rif1, or disruption of its interaction with PP1/Glc7 phosphatase, leads to more intensive rDNA replication. The effect of Rif1-Glc7 on rDNA replication is similar to that of the Sir2 deacetylase, and the two would appear to act in the same pathway, since the rif1Δ sir2Δ double mutant shows no further increase in rDNA replication...
November 2016: PLoS Genetics
Ali Bakr, Sabrina Köcher, Jennifer Volquardsen, Cordula Petersen, Kerstin Borgmann, Ekkehard Dikomey, Kai Rothkamm, Wael Y Mansour
End processing at DNA double strand breaks (DSB) is a decisive step in repair pathway selection. Here, we investigated the role of 53BP1/RIF1 in limiting BRCA1/CtIP-mediated end resection to control DSB repair pathway choice. ATM orchestrates this process through 53BP1 phosphorylation to promote RIF1 recruitment. As cells enter S/G2-phase, end resection is activated, which displaces pATM from DSB sites and diminishes 53BP1 phosphorylation and RIF1 recruitment. Consistently, the kinetics of ATM and 53BP1 phosphorylation in S/G2-phase concur...
August 2, 2016: Oncotarget
Yi-Min Duan, Bo-O Zhou, Jing Peng, Xia-Jing Tong, Qiong-Di Zhang, Jin-Qiu Zhou
In the budding yeast Saccharomyces cerevisiae, heterochromatin structure is found at three chromosome regions, which are homothallic mating-type loci, rDNA regions and telomeres. To address how telomere heterochromatin is assembled under physiological conditions, we employed a de novo telomere addition system, and analyzed the dynamic chromatin changes of the TRP1 reporter gene during telomere elongation. We found that integrating a 255-bp, but not an 81-bp telomeric sequence near the TRP1 promoter could trigger Sir2 recruitment, active chromatin mark(s)' removal, chromatin compaction and TRP1 gene silencing, indicating that the length of the telomeric sequence inserted in the internal region of a chromosome is critical for determining the chromatin state at the proximal region...
July 20, 2016: Journal of Genetics and Genomics, Yi Chuan Xue Bao
Nimna S Ranatunga, Susan L Forsburg
The minichromosome maintenance (MCM) complex is the conserved helicase motor of the eukaryotic replication fork. Mutations in the Mcm4 subunit are associated with replication stress and double strand breaks in multiple systems. In this work, we characterize a new temperature-sensitive allele of Schizosaccharomyces pombe mcm4(+) Uniquely among known mcm4 alleles, this mutation causes sensitivity to the alkylation damaging agent methyl methanesulfonate (MMS). Even in the absence of treatment or temperature shift, mcm4-c106 cells show increased repair foci of RPA and Rad52, and require the damage checkpoint for viability, indicating genome stress...
October 13, 2016: G3: Genes—Genomes—Genetics
Sophie Zaaijer, Nadeem Shaikh, Rishi Kumar Nageshan, Julia Promisel Cooper
Clearance of entangled DNA from the anaphase mid-region must accurately proceed in order for chromosomes to segregate with high fidelity. Loss of Taz1 (fission yeast ortholog of human TRF1/TRF2) leads to stalled telomeric replication forks that trigger telomeric entanglements; the resolution of these entanglements fails at ≤20°C. Here, we investigate these entanglements and their promotion by the conserved replication/repair protein Rif1. Rif1 plays no role in taz1Δ fork stalling. Rather, Rif1 localizes to the anaphase mid-region and regulates the resolution of persisting DNA structures...
June 28, 2016: Cell Reports
Martin Zofall, Deborah R Smith, Takeshi Mizuguchi, Jothy Dhakshnamoorthy, Shiv I S Grewal
Facultative heterochromatin regulates gene expression, but its assembly is poorly understood. Previously, we identified facultative heterochromatin islands in the fission yeast genome and found that RNA elimination machinery promotes island assembly at meiotic genes. Here, we report that Taz1, a component of the telomere protection complex Shelterin, is required to assemble heterochromatin islands at regions corresponding to late replication origins that are sites of double-strand break formation during meiosis...
June 16, 2016: Molecular Cell
Ting-Wei Will Chiang, Carlos le Sage, Delphine Larrieu, Mukerrem Demir, Stephen P Jackson
The RNA-guided Cas9 nuclease is being widely employed to engineer the genomes of various cells and organisms. Despite the efficient mutagenesis induced by Cas9, off-target effects have raised concerns over the system's specificity. Recently a "double-nicking" strategy using catalytic mutant Cas9(D10A) nickase has been developed to minimise off-target effects. Here, we describe a Cas9(D10A)-based screening approach that combines an All-in-One Cas9(D10A) nickase vector with fluorescence-activated cell sorting enrichment followed by high-throughput genotypic and phenotypic clonal screening strategies to generate isogenic knockouts and knock-ins highly efficiently, with minimal off-target effects...
2016: Scientific Reports
Stefano Mattarocci, Lukas Hafner, Aleksandra Lezaja, Maksym Shyian, David Shore
Rap1-interacting factor 1 (Rif1) was originally identified in the budding yeast Saccharomyces cerevisiae as a telomere-binding protein that negatively regulates telomerase-mediated telomere elongation. Although this function is conserved in the distantly related fission yeast Schizosaccharomyces pombe, recent studies, both in yeasts and in metazoans, reveal that Rif1 also functions more globally, both in the temporal control of DNA replication and in DNA repair. Rif1 proteins are large and characterized by N-terminal HEAT repeats, predicted to form an elongated alpha-helical structure...
2016: Frontiers in Genetics
Yuan Xue, Marcus E Marvin, Iglika G Ivanova, David Lydall, Edward J Louis, Laura Maringele
Telomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition...
June 2016: Aging Cell
Easwaran Sreesankar, Vellaichamy Bharathi, Rakesh K Mishra, Krishnaveni Mishra
No abstract text is available yet for this article.
2016: Scientific Reports
Paulina Strzyz
No abstract text is available yet for this article.
February 2016: Nature Reviews. Molecular Cell Biology
Hiromu Tanaka, Akihiko Muto, Hiroki Shima, Yasutake Katoh, Nicolas Sax, Shinya Tajima, Andrey Brydun, Tsuyoshi Ikura, Naoko Yoshizawa, Hisao Masai, Yutaka Hoshikawa, Tetsuo Noda, Masaki Nio, Kyoko Ochiai, Kazuhiko Igarashi
B lymphocyte-induced maturation protein 1 (Blimp-1) encoded by Prdm1 is a master regulator of plasma cell differentiation. The transcription factor Bach2 represses Blimp-1 expression in B cells to stall terminal differentiation, by which it supports reactions such as class switch recombination of the antibody genes. We found that histones H3 and H4 around the Prdm1 intron 5 Maf recognition element were acetylated at higher levels in X63/0 plasma cells expressing Blimp-1 than in BAL17 mature B cells lacking its expression...
March 18, 2016: Journal of Biological Chemistry
Joana B Serrano, Odete A B da Cruz E Silva, Sandra Rebelo
Lamina-associated polypeptide 1 (LAP1) is a type II transmembrane protein of the inner nuclear membrane encoded by the human gene TOR1AIP1. LAP1 is involved in maintaining the nuclear envelope structure and appears be involved in the positioning of lamins and chromatin. To date, LAP1's precise function has not been fully elucidated but analysis of its interacting proteins will permit unraveling putative associations to specific cellular pathways and cellular processes. By assessing public databases it was possible to identify the LAP1 interactome, and this was curated...
2016: Membranes
Tatsuya Kibe, Michal Zimmermann, Titia de Lange
The regulation of 5' end resection at DSBs and telomeres prevents genome instability. DSB resection is positively and negatively regulated by ATM signaling through CtIP/MRN and 53BP1-bound Rif1, respectively. Similarly, telomeres lacking TRF2 undergo ATM-controlled CtIP-dependent hyper-resection when the repression by 53BP1/Rif1 is alleviated. However, telomere resection in the absence of 53BP1/Rif1 is more extensive upon complete removal of shelterin, indicating additional protection against resection by shelterin...
January 21, 2016: Molecular Cell
Haoxing Zhang, Hailong Liu, Yali Chen, Xu Yang, Panfei Wang, Tongzheng Liu, Min Deng, Bo Qin, Cristina Correia, Seungbaek Lee, Jungjin Kim, Melanie Sparks, Asha A Nair, Debra L Evans, Krishna R Kalari, Pumin Zhang, Liewei Wang, Zhongsheng You, Scott H Kaufmann, Zhenkun Lou, Huadong Pei
BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1...
2016: Nature Communications
Rossana Foti, Stefano Gnan, Daniela Cornacchia, Vishnu Dileep, Aydan Bulut-Karslioglu, Sarah Diehl, Andreas Buness, Felix A Klein, Wolfgang Huber, Ewan Johnstone, Remco Loos, Paul Bertone, David M Gilbert, Thomas Manke, Thomas Jenuwein, Sara C B Buonomo
DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains...
January 21, 2016: Molecular Cell
Michelle L Larin, Katherine Harding, Elizabeth C Williams, Noel Lianga, Carole Doré, Sophie Pilon, Éric Langis, Corey Yanofsky, Adam D Rudner
Changes in the locations and boundaries of heterochromatin are critical during development, and de novo assembly of silent chromatin in budding yeast is a well-studied model for how new sites of heterochromatin assemble. De novo assembly cannot occur in the G1 phase of the cell cycle and one to two divisions are needed for complete silent chromatin assembly and transcriptional repression. Mutation of DOT1, the histone H3 lysine 79 (K79) methyltransferase, and SET1, the histone H3 lysine 4 (K4) methyltransferase, speed de novo assembly...
November 2015: PLoS Genetics
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