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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
Emilie Renaud, Aurelia Barascu, Filippo Rosselli
To rescue collapsed replication forks cells utilize homologous recombination (HR)-mediated mechanisms to avoid the induction of gross chromosomal abnormalities that would be generated by non-homologous end joining (NHEJ). Using DNA interstrand crosslinks as a replication barrier, we investigated how the Fanconi anemia (FA) pathway promotes HR at stalled replication forks. FA pathway inactivation results in Fanconi anemia, which is associated with a predisposition to cancer. FANCD2 monoubiquitination and assembly in subnuclear foci appear to be involved in TIP60 relocalization to the chromatin to acetylates histone H4K16 and prevents the binding of 53BP1 to its docking site, H4K20Me2...
January 29, 2016: Nucleic Acids Research
Yutaka Kanoh, Seiji Matsumoto, Rino Fukatsu, Naoko Kakusho, Nobuaki Kono, Claire Renard-Guillet, Koji Masuda, Keisuke Iida, Kazuo Nagasawa, Katsuhiko Shirahige, Hisao Masai
Rif1 regulates replication timing and repair of double-strand DNA breaks. Using a chromatin immunoprecipitation-sequencing method, we identified 35 high-affinity Rif1-binding sites in fission yeast chromosomes. Binding sites tended to be located near dormant origins and to contain at least two copies of a conserved motif, CNWWGTGGGGG. Base substitution within these motifs resulted in complete loss of Rif1 binding and in activation of late-firing or dormant origins located up to 50 kb away. We show that Rif1-binding sites adopt G quadruplex-like structures in vitro, in a manner dependent on the conserved sequence and on other G tracts, and that purified Rif1 preferentially binds to this structure...
November 2015: Nature Structural & Molecular Biology
Yafei Qi, Jun Zhao, Rui An, Juan Zhang, Shuang Liang, Jingxia Shao, Xiayan Liu, Lijun An, Fei Yu
Leaf variegation mutants constitute a unique group of chloroplast development mutants and are ideal genetic materials to dissect the regulation of chloroplast development. We have utilized the Arabidopsis yellow variegated (var2) mutant and genetic suppressor analysis to probe the mechanisms of chloroplast development. Here we report the isolation of a new var2 suppressor locus SUPPRESSOR OF VARIEGATION (SVR10). Genetic mapping and molecular complementation indicated that SVR10 encodes a circularly permuted GTPase that has been reported as Arabidopsis thaliana NITRIC OXIDE ASSOCIATED 1 (AtNOA1) and RESISTANT TO INHIBITION BY FOSMIDOMYCIN 1 (RIF1)...
March 2016: Photosynthesis Research
Hannah Kaizer, Carla J Connelly, Kelsey Bettridge, Christopher Viggiani, Carol W Greider
The regulation of telomere length equilibrium is essential for cell growth and survival since critically short telomeres signal DNA damage and cell cycle arrest. While the broad principles of length regulation are well established, the molecular mechanism of how these steps occur is not fully understood. We mutagenized the RIF2 gene in Saccharomyces cerevisiae to understand how this protein blocks excess telomere elongation. We identified an N-terminal domain in Rif2 that is essential for length regulation, which we have termed BAT domain for Blocks Addition of Telomeres...
October 2015: Genetics
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