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Focus on Cell cycle and DNA damage
The maintenance of genomic integrity requires tight control of the cell division process as well as accurate repair of damaged DNA, and failure in such mechanisms can cause developmental disorders and cancer. In the October issue of Nature Cell Biology, leading scientists highlight and discuss new developments in these areas.
Access the Focus online for FREE in October:
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| | | | Editorial |  Top | |  | | | | Articles | Top | | | | Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8 pp1323 - 1330
Seung Beom Hong, Byeong-Won Kim, Kyung-Eun Lee, Se Woong Kim, Hyesung Jeon, Joon Kim and Hyun Kyu Song
doi:10.1038/nsmb.2165
The mechanism by which the noncanonical E1-like enzyme Atg7 activates ubiquitin-like Atg8 to trigger autophagy has not been well understood. The crystal structures of the N-terminal domain of Atg7 alone and C-terminal domain of Atg7 in complex with Atg8 show that this probably proceeds without the need for dramatic conformational rearrangements by Atg7, distinct from other E1 enzymes.
Abstract | Full Text | PDF
| | | | Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors pp1331 - 1335
Matilde Murga, Stefano Campaner, Andres J Lopez-Contreras, Luis I Toledo, Rebeca Soria, Maria F Montaña, Luana D'Artista, Thomas Schleker, Carmen Guerra, Elena Garcia, Mariano Barbacid, Manuel Hidalgo, Bruno Amati and Oscar Fernandez-Capetillo
doi:10.1038/nsmb.2189
Oncogenic activation can generate replicative stress, leading to activation of ATR and Chk1. The hypothesis that these events could be exploited to selectively kill cancer cells is now demonstrated in vivo, using mouse models for cancer development. Myc-driven tumors are shown to be sensitive to ATR deficiency or inhibition of Chk1.
Abstract | Full Text | PDF
| | | | Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein pp1336 - 1344
Hye-Ra Lee, Won-Chan Choi, Stacy Lee, Jungwon Hwang, Eunha Hwang, Koushik Guchhait, Juergen Haas, Zsolt Toth, Young Ho Jeon, Tae-Kwang Oh, Myung Hee Kim and Jae U Jung
doi:10.1038/nsmb.2142
Restoration of p53 activity is a promising chemotherapeutic approach, and because of the high binding affinity between HAUSP, MDM2 and p53, blocking HAUSP activity should have the net effect of robust p53 stabilization. HAUSP is inhibited by belt-like binding of vIRF4 from Kaposi's sarcoma-associated herpesvirus. Two peptides derived from vIRF4 can additively inhibit HAUSP, leading to p53-dependent cell cycle arrest and xenograft tumor regression.
Abstract | Full Text | PDF
| | | | The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks pp1345 - 1350
Klara Acs, Martijn S Luijsterburg, Leena Ackermann, Florian A Salomons, Thorsten Hoppe and Nico P Dantuma
doi:10.1038/nsmb.2188
The E3 ubiquitin ligases RNF8 and RNF168 are required for recruitment of tumor surpressor 53BP1 to sites of DNA double-strand breaks. The reasons for this have been unclear, as 53BP1 recognizes histone mark H4K20me2. Now the AAA-ATPase VCP and cofactors are shown to be recruited in a ubiquitination-dependent manner to double-strand break sites, where they remove polycomb protein L3MBTL1 from chromatin.
Abstract | Full Text | PDF
| | | | The Chp1–Tas3 core is a multifunctional platform critical for gene silencing by RITS pp1351 - 1357
Thomas Schalch, Godwin Job, Sreenath Shanker, Janet F Partridge and Leemor Joshua-Tor
doi:10.1038/nsmb.2151
The RITS complex links the RNAi pathway with centromeric heterochromatin formation in fission yeast and comprises the chromodomain protein Chp1, the GW protein Tas3 and the argonaute protein Ago1. X-ray analysis of the structured core of the Chp1–Tas3 subcomplex reveals the presence of a C-terminal PIN domain in Chp1, which contributes to post-transcriptional gene silencing of subtelomeric transcripts independently of RNAi.
Abstract | Full Text | PDF
| | | | Recognition of enhancer element–specific histone methylation by TIP60 in transcriptional activation pp1358 - 1365
Kwang Won Jeong, Kyunghwan Kim, Alan Jialun Situ, Tobias S Ulmer, Woojin An and Michael R Stallcup
doi:10.1038/nsmb.2153
Histone acetyltransferase Tip60 is required to activate several target genes of ERα. Now Tip60 is shown to interact directly with ERα and to recognize the enhancer marker H3K4me1, leading to transcriptional activation in response to estrogen.
Abstract | Full Text | PDF
| | | | Structure of green-type Rubisco activase from tobacco pp1366 - 1370
Mathias Stotz, Oliver Mueller-Cajar, Susanne Ciniawsky, Petra Wendler, F Ulrich Hartl, Andreas Bracher and Manajit Hayer-Hartl
doi:10.1038/nsmb.2171
The enzyme Rubisco has a central role in atmospheric CO2 fixation. Rubisco can be inactivated if its sugar substrate is bound prior to carbamylation of a residue in the active site. The structure of tobacco Rca, the enzyme that removes the bound sugar substrate and activates Rubisco, is now presented, offering insight into this process.
Abstract | Full Text | PDF
| | | | The RNA accordion model for template positioning by telomerase RNA during telomeric DNA synthesis pp1371 - 1375
Andrea J Berman, Benjamin M Akiyama, Michael D Stone and Thomas R Cech
doi:10.1038/nsmb.2174
Telomerase uses its associated RNA as a template for processive addition of telomeric DNA repeats. Biochemistry and smFRET analysis are now used to investigate how the RNA template moves along the active site, revealing an accordion mechanism whereby the regions flanking the template alternate between extended and compacted forms.
Abstract | Full Text | PDF
| | | | Structural basis for the molecular evolution of SRP-GTPase activation by protein pp1376 - 1380
Gert Bange, Nico Kümmerer, Przemyslaw Grudnik, Robert Lindner, Georg Petzold, Dieter Kressler, Ed Hurt, Klemens Wild and Irmgard Sinning
doi:10.1038/nsmb.2141
SRP-type GTPases deviate from other GTPases in that they are not activated by GTPase-activating proteins (GAPs). New studies show that the MinD-type protein YlxH activates the SRP-GTPase FlhF, which is involved in flagellar biosynthesis. The crystal structure of the Bacillus subtilis FlhF–effector complex reveals the mechanism of activation, the general concept of which may also apply to RNA-mediated activation of the SRP-GTPases Ffh and FtsY.
Abstract | Full Text | PDF
| | | | NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling pp1381 - 1387
Peter D Mace, Yann Wallez, Malgorzata K Dobaczewska, JeongEun J Lee, Howard Robinson, Elena B Pasquale and Stefan J Riedl
doi:10.1038/nsmb.2152
NSP and Cas family proteins form multidomain signaling platforms that integrate signals to mediate cell migration and invasion. Structural analyses show that the C-terminal domain of human NSP protein BCAR3 adopts the Cdc25-homology fold of Ras GTPase exchange factors, but in a closed conformation incompatible with enzymatic activity. Instead, this closed conformation is instrumental for interactions with Cas proteins.
Abstract | Full Text | PDF
| | | | Mechanistic insights into the activation of oncogenic forms of EGF receptor pp1388 - 1393
Zhihong Wang, Patti A Longo, Mary Katherine Tarrant, Kwangsoo Kim, Sarah Head, Daniel J Leahy and Philip A Cole
doi:10.1038/nsmb.2168
The EGFR receptor tyrosine kinase is frequently mutated in lung cancer, but the mechanism by which mutations activate kinase activity are not clear. Using purified, nearly full-length EGFR, it is now seen that mutations drive activation and resistance to inhibitors through the formation of the asymmetric kinase domain dimer.
Abstract | Full Text | PDF
| | | | The elongation rate of RNA polymerase determines the fate of transcribed nucleosomes pp1394 - 1399
Lacramioara Bintu, Marta Kopaczynska, Courtney Hodges, Lucyna Lubkowska, Mikhail Kashlev and Carlos Bustamante
doi:10.1038/nsmb.2164
What happens to histones during transcription is not well understood. Atomic force microscopy snapshots of RNA polymerase II (Pol II)-nucleosome complexes before, during and after transcription show the presence of looped transcriptional intermediates. In addition, a fraction of transcribed histones are remodeled to hexasomes, and the size of this fraction depends on the elongation rate of Pol II.
Abstract | Full Text | PDF
| | | | The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection pp1400 - 1407
Rekha Rai, Ju-Mei Li, Hong Zheng, Gabriel Tsz-Mei Lok, Yu Deng, Michael S-Y Huen, Junjie Chen, Jianping Jin and Sandy Chang
doi:10.1038/nsmb.2172
Rnf8 is an E3 ligase involved in the DNA damage response, adding ubiquitin moieties to histones H2A and H2AX at sites of DNA damage. Now Rnf8 is found to modify shelterin subunit Tpp1, and this is important for its stability and retention at telomeres. Cells lacking Rnf8 show telomere shortening and chromosome fusions.
Abstract | Full Text | PDF
| | | | Tel1ATM and Rad3ATR kinases promote Ccq1-Est1 interaction to maintain telomeres in fission yeast pp1408 - 1413
Bettina A Moser, Ya-Ting Chang, Jorgena Kosti and Toru M Nakamura
doi:10.1038/nsmb.2187
In fission yeast, the DNA damage kinases Tel1 (ATM) and Rad3 (ATR) are required to recruit telomerase to telomere. The relevant target for these kinases is now identified: shelterin subunit Ccq1 is phosphorylated at Thr93 in a Tel1/Rad3-dependent manner, and this modification is essential for Ccq1 to interact with telomerase subunit Est1.
Abstract | Full Text | PDF
| | | | Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins pp1414 - 1420
Konstantinos Tripsianes, Tobias Madl, Martin Machyna, Dimitrios Fessas, Clemens Englbrecht, Utz Fischer, Karla M Neugebauer and Michael Sattler
doi:10.1038/nsmb.2185
Dimethylated arginine (DMA) marks are recognized by Tudor domain-containing proteins and play a role in the assembly of ribonucleoprotein complexes. Structural analysis of prototypic Tudor domains from SMN and SPF30 in complex with DMA reveals the recognition mode of DMA, enabling the design of an optimized binding pocket.
Abstract | Full Text | PDF
| | Brief Communications | Top | | | | Molecular profiling of common fragile sites in human fibroblasts pp1421 - 1423
Benoî Le Tallec, Bernard Dutrillaux, Anne-Marie Lachages, Gael Armel Millot, Olivier Brison and Michelle Debatisse
doi:10.1038/nsmb.2155
Common fragile sites (CFSs) can drive genomic instability. The basis for their fragile nature is not clear, but lymphocyte CFSs have been mapped to regions with low replication initiation events and late replication completion. These features are now used to rapidly identify CFSs in different fibroblast cells.
Abstract | Full Text | PDF
| | | | A shared structural solution for neutralizing ebolaviruses pp1424 - 1427
João M Dias, Ana I Kuehne, Dafna M Abelson, Shridhar Bale, Anthony C Wong, Peter Halfmann, Majidat A Muhammad, Marnie L Fusco, Samantha E Zak, Eugene Kang, Yoshihiro Kawaoka, Kartik Chandran, John M Dye and Erica Ollmann Saphire
doi:10.1038/nsmb.2150
The surface glycoprotein of the distinct ebolavirus responsible for the largest outbreak yet described (Sudan Gulu) has been crystallized in complex with a novel, neutralizing antibody. The crystal structure and accompanying in vitro and in vivo experiments demonstrate that the antibody functions after virus entry and illustrates a key hotspot for ebolavirus neutralization.
Abstract | Full Text | PDF
| | | | RNA targets of wild-type and mutant FET family proteins pp1428 - 1431
Jessica I Hoell, Erik Larsson, Simon Runge, Jeffrey D Nusbaum, Sujitha Duggimpudi, Thalia A Farazi, Markus Hafner, Arndt Borkhardt, Chris Sander and Thomas Tuschl
doi:10.1038/nsmb.2163
The FET family proteins FUS, EWSR1 and TAF15 are RNA-binding proteins with diverse nuclear functions. PAR-CLIP analyses now reveal the genome-wide RNA targets of all three human FET proteins and of two FUS mutants that cause amyotrophic lateral sclerosis. Although the RNA-binding properties of the mutants remain unchanged, the spectrum of RNA targets is altered because of the changed subcellular localization of the mutants.
Abstract | Full Text | PDF
| | | | Formaldehyde catabolism is essential in cells deficient for the Fanconi anemia DNA-repair pathway pp1432 - 1434
Ivan V Rosado, Frédéric Langevin, Gerry P Crossan, Minoru Takata and Ketan J Patel
doi:10.1038/nsmb.2173
The Fanconi anemia (FA) DNA-repair pathway is important in processing of DNA interstrand cross-links and in resistance to exogenously added aldehyde. Genetic analyses now reveal the synthetic lethality of deficiencies in the FA pathway and formaldehyde catabolism, indicting that this pathway repairs lesions caused by endogenous formaldehyde.
Abstract | Full Text | PDF
| | Resource | Top | | | | Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain pp1435 - 1440
Adam Ameur, Ammar Zaghlool, Jonatan Halvardson, Anna Wetterbom, Ulf Gyllensten, Lucia Cavelier and Lars Feuk
doi:10.1038/nsmb.2143
Co-transcriptional splicing has been seen in lower eukaryotes as well as for a few mammalian genes, but the extent to which it affects mammalian gene regulation has been unclear. RNA sequencing now shows that co-transcriptional splicing is widespread in human cells and particularly abundant in the human brain.
Abstract | Full Text | PDF
| | | Top | | | | Advertisement | | Please take a look at Molecular Systems Biology's most downloaded article!
Engineered microbes that sense and kill a pathogen
Nazanin Saeidi et al.
Mol. Sys. Bio. 7:521
A synthetic genetic system is designed and characterized that allows Escherichia coli to sense and eradicate Pseudomonas aeruginosa, providing a novel antimicrobial strategy that could potentially be applied to fighting infectious pathogens. |
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