Table of Contents

Volume 10, Issue 9

  May 1, 2011

  Pages 1335 - 1503

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 Issue Catalogue (MARC XML)

EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Connection between induction of DNA lesions and DNA recombination/repair during Ig class switch recombination

Sven Kracker and Anne Durandy
Pages 1335 - 1336
http://dx.doi.org/10.4161/cc.10.9.15290
Abstract | PDF

Comment on: Kracker S, et al. Proc Natl Acad Sci USA 2010; 107:22225-30.

Open Access Article

Regulation of the autophagy initiating kinase ULK1 by nutrients: Roles of mTORC1 and AMPK

Joungmok Kim and Kun-Liang Guan
Pages 1337 - 1338
http://dx.doi.org/10.4161/cc.10.9.15291
Abstract | PDF

Comment on: Kim J, et al. Nat Cell Biol 2011; 13:132-41.

Open Access Article

DNA knots and DNA supercoiling

Guillaume Witz, Giovanni Dietler and Andrzej Stasiak
Pages 1339 - 1340
http://dx.doi.org/10.4161/cc.10.9.15293
Abstract | PDF

Comment on: Witz G, et al. Proc Natl Acad Sci USA 2011; 108:3608-11.

Open Access Article

JAML and CAR: Two more players in T-cell activation

Petra Verdino and Ian A. Wilson
Pages 1341 - 1342
http://dx.doi.org/10.4161/cc.10.9.15294
Abstract | PDF

Comment on: Verdino P, et al. Science 2010; 329:1210-4.

Open Access Article

Roles of protein arginine methylation in DNA damage signaling pathways: Is CARM1 a life-or-death decision point?

Young-Ho Lee and Michael R. Stallcup
Pages 1343 - 1344
http://dx.doi.org/10.4161/cc.10.9.15379
Abstract | PDF

Comment on: Lee YH, et al. Genes Dev 2011; 25:176-88.

Open Access Article

In the right place at the right time: Analysis of p53 serine 312 phosphorylation in vivo

Elizabeth A. Slee and Xin Lu
Pages 1345 - 1346
http://dx.doi.org/10.4161/cc.10.9.15347
Abstract | PDF

Comment on: Slee EA, et al. Proc Natl Acad Sci USA 2010; 107:19479–84.




CELL CYCLE NEWS & VIEWS

Open Access Article

Decreased Mdm2 levels after DNA damage: Antibody masking or protein degradation?

Christine M. Eischen
Pages 1347 - 1351
http://dx.doi.org/10.4161/cc.10.9.15437
Abstract | PDF

Comment on: Cheng Q, et al. Cell Cycle 2011: 10:1162-6.

Open Access Article

Beyond immune surveillance: Stat1 limits tumor growth in a cell-autonomous fashion

Josie Ursini-Siegel

http://dx.doi.org/10.4161/cc.10.9.15435
Abstract | PDF

Comment on: Raven JF, et al. Cell Cycle 2011; 10:794-804.

Open Access Article

Cell cycle transitions and Cdk inhibition in melanoma therapy: Cyclin' through the options

Michael B. Mann and Philipp Kaldis

http://dx.doi.org/10.4161/cc.10.9.15381
Abstract | PDF

Comment on: Abdullah C, et al. Cell Cycle 2011; 10:977-88.

Open Access Article

Flying to a halt: Drosophila Aven arrests the cell cycle

Brian A. Roelofs and J. Marie Hardwick

http://dx.doi.org/10.4161/cc.10.9.15436
Abstract | PDF

Comment on: Zou S, et al. Cell Cycle 2011; 10: 989-98.

Open Access Article

p73 and p63: Estranged relatives?

Fadel Tissir and André M. Goffinet

http://dx.doi.org/10.4161/cc.10.9.15383
Abstract | PDF

Comment on: Holembowski L, et al. Cell Cycle 2011; 10:680-9.




EXTRA VIEWS

Open Access Article

Tissue-specific apoptotic effects of the p53 codon 72 polymorphism in a mouse model

Gregory A. Azzam, Amanda K. Frank, Monica Hollstein and Maureen E. Murphy
Pages 1352 - 1355
http://dx.doi.org/10.4161/cc.10.9.15344
Abstract | PDF

Currently there are several dozen human polymorphisms that have been loosely associated with cancer risk. Correlating such variants with cancer risk has been challenging, primarily due to factors such as genetic heterogeneity, contributions of diet and environmental factors, and the difficulty in obtaining large sample sizes for analysis. Such difficulties can be circumvented with the establishment of mouse models for human variants. Recently, several groups have modeled human cancer susceptibility polymorphisms in the mouse. Remarkably, in each case these mouse models have accurately reflected human phenotypes, and clarified the contribution of these variants to cancer risk. We recently reported on a mouse model for the codon 72 polymorphism in p53, and found that this polymorphism regulates the ability to cooperate with NF-kB and induce apoptosis. Here-in we present evidence that this polymorphism impacts the apoptotic function of p53 in a tissue-specific manner; such tissue-specific effects of polymorphic variants represent an added challenge to human cancer risk association studies. The data presented here support the premise that modeling human polymorphisms in the mouse represents a powerful tool to assess the impact of these variants on cancer risk, progression and therapy.

Open Access Article

Protein phosphatase 1 regulators in DNA damage signaling

Thomas Küntziger, Helga B. Landsverk, Philippe Collas and Randi G. Syljuåsen
Pages 1356 - 1362
http://dx.doi.org/10.4161/cc.10.9.15442
Abstract | PDF

In response to DNA damaging agents and endogenous DNA lesions, human cells activate signaling cascades and repair mechanisms to help maintain genomic integrity. Phosphorylation plays a major role in DNA damage signaling, and the role of Ser/Thr kinases, including ATM, ATR, CHK1, CHK2 and DNA-PK, is particularly well documented. While these kinases have taken the center stage in DNA damage signaling until now, a role for Ser/Thr phosphatases is emerging, including Protein Phosphatase 1 (PP1). PP1 substrate specificity is regulated by its binding to a large number of different targeting subunits, and several of these have recently been identified as regulators of DNA damage responses. Here we review recent progress regarding the involvement of PP1 and its binding partners in DNA damage signaling.

Open Access Article

The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis

Xiao Z. Shen and Kenneth E. Bernstein
Pages 1363 - 1369
http://dx.doi.org/10.4161/cc.10.9.15444
Abstract | PDF




The concept of a local bone marrow renin-angiotensin system (RAS) has been introduced and accumulating evidence suggests that the local RAS is actively involved in hematopoiesis. Angiotensin converting enzyme (ACE) is a key player in the RAS and makes the final effector angiotensin II. Besides angiotensin II, ACE also regulates a panel of bioactive peptides, such as substance P, Ac-SDKP and angiotensin 1-7. These peptides have also been individually reported in the regulation of pathways of hematopoiesis. In this setting, an ACE-regulated peptide network orchestrating hematopoiesis has emerged. Here, we focus on this peptide network and discuss the roles of ACE and its peptides in aspects of hematopoiesis. Special attention is given to the recent revelation that ACE is a bona fide marker of hematopoietic stem cells.  

Open Access Article

Endothelial origin of mesenchymal stem cells

Igor I. Slukvin and Maxim Vodyanik
Pages 1370 - 1373
http://dx.doi.org/10.4161/cc.10.9.15345
Abstract | PDF

Mesenchymal stem/stromal cells (MSCs) are fibroblastoid cells capable of long-term expansion and skeletogenic differentiation. While MSCs are known to originate from neural crest and mesoderm, immediate mesodermal precursors that give rise to MSCs have not been characterized. Recently, using human embryonic stem cells (hESCs), we demonstrated that mesodermal MSCs arise from APLNR+ precursors with angiogenic potential, mesenchymoangioblasts, which can be identified by FGF2-dependent colony-forming assay in serum-free semisolid medium. In this overview we provide additional insights on cellular pathways leading to MSC establishment from mesoderm, with special emphasis on endothelial-mesenchymal transition as a critical step in MSC formation. In addition, we highlight an essential role of FGF2 in induction of angiogenic cells with potential to transform into MSCs (mesenchymoangioblasts) or hematopoietic cells (hemangioblasts) from mesoderm, and discuss correlations of our in vitro findings with the course of angioblast development during embryogenesis.

Open Access Article

Regulation of the final stage of mitosis by components of the pre-replicative complex and a polo kinase

Hyungshin Yim and Raymond L. Erikson
Pages 1374 - 1377
http://dx.doi.org/10.4161/cc.10.9.15489
Abstract | PDF

The accurate division of duplicated DNA is essential for maintenance of genomic stability in proliferating eukaryotic cells. Errors in DNA replication and chromosomal segregation may lead to cell death or genomic mutations that lead to oncogenic properties. Thus, tight regulation of DNA replication and mitosis is essential for maintaining genomic integrity. Cell division cycle 6 (Cdc6) is an essential factor for initiating DNA replication. Recent work shows that phosphorylation of Cdc6 by polo-like kinase 1 (Plk1), one of the essential mitotic kinases, regulates mitotic exit mediated by Cdk1 and separase. Here we discuss how pre-replicative complex factors are connected with Plk1 and affect mitotic exit.




REVIEW

Open Access Article

Aldehyde dehydrogenase: Its role as a cancer stem cell marker comes down to the specific isoform

Paola Marcato, Cheryl A. Dean, Carman A. Giacomantonio and Patrick W.K. Lee
Pages 1378 - 1384
http://dx.doi.org/10.4161/cc.10.9.15486
Abstract | PDF

Recent evidence suggests that enhanced aldehyde dehydrogenase (ALDH) activity is a hallmark of cancer stem cells (CSC) measurable by the aldefluor assay. ALDH1A1, one of 19 ALDH isoforms expressed in humans, was generally believed to be responsible for the ALDH activity of CSCs. More recently, experiments with murine hematopoietic stem cells, murine progenitor pancreatic cells, and human breast CSCs indicate that other ALDH isoforms, particularly ALDH1A3, significantly contribute to aldefluor positivity, which may be tissue and cancer specific. Therefore, potential prognostic application involving the use of CSC prevalence in tumor tissue to predict patient outcome requires the identification and quantification of specific ALDH isoforms. Herein we review the suggested roles of ALDH in CSC biology and the immunohistological studies testing the potential application of ALDH isoforms as novel cancer prognostic indicators.




REPORTS

Open Access Article

A genomic analysis of chronological longevity factors in budding yeast

Christopher R. Burtner, Christopher J. Murakami, Brady Olsen, Brian K. Kennedy and Matt Kaeberlein
Pages 1385 - 1396
http://dx.doi.org/10.4161/cc.10.9.15464
Abstract | PDF

Chronological life span (CLS) has been studied as an aging paradigm in yeast. A few conserved aging genes have been identified that modulate both chronological and replicative longevity in yeast as well as longevity in the nematode Caenorhabditis elegans; however, a comprehensive analysis of the relationship between genetic control of chronological longevity and aging in other model systems has yet to be reported. To address this question, we performed a functional genomic analysis of chronological longevity for 550 single-gene deletion strains, which accounts for approximately 12% of the viable homozygous diploid deletion strains in the yeast ORF deletion collection. This study identified 33 previously unknown determinants of CLS. We found no significant enrichment for enhanced CLS among deletions corresponding to yeast orthologs of worm aging genes or among replicatively long-lived deletion strains, although a trend toward overlap was noted. In contrast, a subset of gene deletions identified from a screen for reduced acidification of culture media during growth to stationary phase was enriched for increased CLS. These results suggest that genetic control of CLS under the most commonly utilized assay conditions does not strongly overlap with longevity determinants in C. elegans, with the existing confined to a small number of genetic pathways. These data also further support the model that acidification of the culture medium plays an important role in survival during chronological aging in synthetic medium, and suggest that chronological aging studies using alternate medium conditions may be more informative with regard to aging of multicellular eukaryotes.

Open Access Article

Alzheimer Aβ disrupts the mitotic spindle and directly inhibits mitotic microtubule motors

Sergiy I. Borysov, Antoneta Granic, Jaya Padmanabhan, Claire E. Walczak and Huntington Potter
Pages 1397 - 1410
http://dx.doi.org/10.4161/cc.10.9.15478
Abstract | PDF

Chromosome mis-segregation and aneuploidy are greatly induced in Alzheimer’s disease and models thereof by mutant forms of the APP and PS proteins and by their product, the Ab peptide. Here we employ human somatic cells and Xenopus egg extracts to show that Aβ impairs the assembly and maintenance of the mitotic spindle. Mechanistically, these defects result from Aβ’s inhibition of mitotic motor kinesins, including Eg5, KIF4A and MCAK. In vitro studies show that oligomeric Aβ directly inhibits recombinant MCAK by a noncompetitive mechanism. In contrast, inhibition of Eg5 and KIF4A is competitive with respect to both ATP and microtubules, indicating that Aβ interferes with their interactions with the microtubules of the mitotic spindle. Consistently, increased levels of polymerized microtubules or of the microtubule stabilizing protein Tau significantly decrease the inhibitory effect of Aβ on Eg5 and KIF4A. Together, these results indicate that by disrupting the interaction between specific kinesins and microtubules and by exerting a direct inhibitory effect on the motor activity, excess Ab deregulates the mechanical forces that govern the spindle and thereby leads to the generation of defective mitotic structures. The resulting defect in neurogenesis can account for the over 30% aneuploid/hyperploid, degeneration-prone neurons observed in Alzheimer disease brain. The finding of mitotic motors including Eg5 in mature post-mitotic neurons implies that their inhibition by Ab may also disrupt neuronal function and plasticity.

Open Access Article

Protein phosphatase PP6 is required for homology-directed repair of DNA double-strand breaks

Jianing Zhong, Ji Liao, Xin Liu, Pei Wang, Jinping Liu, Wenya Hou, Bingtao Zhu, Lu Yao, Jinsheng Wang, Jing Li, Jeremy M. Stark, Yuntao Xie and Xingzhi Xu
Pages 1411 - 1419
http://dx.doi.org/10.4161/cc.10.9.15479
Abstract | PDF

DNA double-strand breaks (DSBs) are among the most lethal lesions associated with genome stability which, when destabilized, predisposes organs to cancers. DSBs are primarily fixed either with little fidelity by non-homologous end joining (NHEJ) repair or with high fidelity by homology-directed repair (HDR). The phosphorylated form of H2AX on serine 139 (g-H2AX) is a marker of DSBs. In this study, we explored if the protein phosphatase PP6 is involved in DSB repair by depletion of its expression in human cancer cell lines, and determined PP6 expression in human breast cancer tissues by immunohistochemistry staining. We found that bacterially-produced PP6c (the catalytic subunit of PP6)-containing heterotrimeric combinations exhibit phosphatase activity against g-H2AX in the in vitro phosphatase assays. Depletion of PP6c or PP6R2 led to persistent high levels of g-H2AX after DNA damage and a defective HDR. Chromatin immunoprecipitation assays demonstrated that PP6c was recruited to the region adjacent to the DSB sites. Expression of PP6c, PP6R2, and PP6R3 in human breast tumors was significantly lower than those in benign breast diseases. Taken together, our results suggest that g-H2AX is a physiological substrate of PP6, and PP6 is required for HDR and its expression may harbor a protective role during the development of breast cancer.

Open Access Article

PP2A^Cdc55 is required for multiple events during meiosis I

Jocelyn K. Nolt, Lyndi M. Rice, Christina Gallo-Ebert, Margaret E. Bisher and Joseph T. Nickels
Pages 1420 - 1434
http://dx.doi.org/10.4161/cc.10.9.15485
Abstract | PDF

Protein phosphatase 2A (PP2A) is a heterotrimer consisting of A and B regulatory subunits and a C catalytic subunit. PP2A regulates mitotic cell events that include the cell cycle, nutrient sensing, p53 stability and various mitogenic signals. The role of PP2A during meiosis is less understood. We explored the role of Saccharomyces cerevisiae PP2A during meiosis. We show a PP2A^Cdc55 containing the human B/55 family B subunit ortholog, Cdc55, is required for progression through meiosis I. Mutant cells lacking Cdc55 remain mononucleated. They harbor meiotic gene expression, premeiotic DNA replication, homologous recombination and spindle pole body (SPB) defects. They initiate but do not complete replication and are defective in performing intergenic homologous recombination. Bypass alleles, which allow cells defective in recombination to finish meiosis, do not suppress the meiosis I defect. cdc55 cells arrest with a single SPB lacking microtubules, or duplicated but not separated SBPs containing microtubules. Finally, the premeiotic replication defect is suppressed by loss of Rad9 checkpoint function. We conclude PP2A^Cdc55 is required for the proper temporal initiation of multiple meiotic events and/or monitors these events to ensure their fidelity.

Open Access Article

The cell cycle inhibitor p27^Kip1 controls self-renewal and pluripotency of human embryonic stem cells by regulating the cell cycle, Brachyury and Twist

Cristina Menchón, Michael J. Edel and Juan Carlos Izpisua Belmonte
Pages 1435 - 1447
http://dx.doi.org/10.4161/cc.10.9.15421
Abstract | Full Text | PDF

The continued turn over of human embryonic stem cells (hESC) while maintaining an undifferentiated state is dependent on the regulation of the cell cycle. Here we asked the question if a single cell cycle gene could regulate the self-renewal or pluripotency properties of hESC. We identified that the protein expression of the p27^Kip1 cell cycle inhibitor is low in hESC cells and increased with differentiation. By adopting a gain and loss of function strategy we forced or reduced its expression in undifferentiating conditions to define its functional role in self-renewal and pluripotency. Using undifferentiation conditions, overexpression of p27^Kip1 in hESC lead to a G₁ phase arrest with an enlarged and flattened hESC morphology and consequent loss of self-renewal ability. Loss of p27^Kip1 caused an elongated/scatter cell-like phenotype involving upregulation of Brachyury and Twist gene expression. We demonstrate the novel finding that p27^Kip1 protein occupies the Twist1 gene promoter and manipulation of p27^Kip1 by gain and loss of function is associated with Twist gene expression changes. These results define p27^Kip1 expression levels as critical for self-renewal and pluripotency in hESC and suggest a role for p27^Kip1 in controlling an epithelial to mesenchymal transition (EMT) in hESC.

Open Access Article

Reversion of gene expression alterations in hearts of mice with chronic chagasic cardiomyopathy after transplantation of bone marrow cells

Milena B.P. Soares, Ricardo S. Lima, Bruno S.F. Souza, Juliana F. Vasconcelos, Leonardo L. Rocha, Ricardo Ribeiro dos Santos, Sanda Iacobas, Regina C. Goldenberg, Michael P. Lisanti, Dumitru A. Iacobas, Herbert B. Tanowitz, David C. Spray and Antonio C. Campos de Carvalho
Pages 1448 - 1455
http://dx.doi.org/10.4161/cc.10.9.15487
Abstract | PDF

Chronic chagasic cardiomyopathy is a leading cause of heart failure in Latin American countries, being associated with intense inflammatory response and fibrosis. We have previously shown that bone marrow mononuclear cell (BMC) transplantation improves inflammation, fibrosis, and ventricular diameter in hearts of mice with chronic Chagas disease. Here we investigated the transcriptomic recovery induced by BMC therapy by comparing the heart transcriptomes of control, chagasic, and BMC transplanted mice. Out of the 9390 unique genes quantified in all samples, 1702 had their expression altered in chronic chagasic hearts compared to those of normal mice. Major categories of significantly upregulated genes were related to inflammation, fibrosis and immune responses, while genes involved in mitochondrion function were downregulated. When BMC-treated chagasic hearts were compared to infected mice, 96% of the alterations detected in infected hearts were restored to normal levels, although an additional 109 genes were altered by treatment. Transcriptomic recovery, a new measure that considers both resotrative and side effects of treatment, was remarkably high (84%). Immunofluorescence and morphometric analyses confirmed the effects of BMC therapy in the pattern of inflammatory-immune response and expression of adhesion molecules. In conclusion, by using large-scale gene profiling for unbiased assessment of therapeutic efficacy we demonstrate immunomodulatory effects of BMC therapy in chronic chagasic cardiomyopathy and identify potentially relevant factors involved in the pathogenesis of the disease that may provide new therapeutic targets.

Open Access Article

RNA export factor RAE1 contributes to NUP98-HOXA9-mediated leukemogenesis

Tatsuyoshi Funasaka, Hiroshi Nakano, Yu Wu, Chieko Hashizume, Ling Gu, Takuro Nakamura, Wei Wang, Pengbo Zhou, Malcolm A.S. Moore, Hiroshi Sato and Richard W. Wong
Pages 1456 - 1467
http://dx.doi.org/10.4161/cc.10.9.15494
Abstract | PDF

Chromosomal translocations involving chimeric fusions of the nucleoporin NUP98 protein have often been described in acute myelogenous leukemia (AML). All the fusion proteins have an identical NUP98 N terminus, which contains the GLEBS motif for interaction with the mRNA export factor RAE1 and FG repeats that associate with the transcription factors HDAC1 and p300. It is virtually unknown whether these interaction partners affect leukemogenesis. We previously showed that RAE1 depletion caused aneuploidy, which enhanced tumorigenesis. We speculated that RAE1 may also be directly involved in NUP98 fusion-mediated leukemogenesis. We show here that RNA interference (RNAi)-mediated knockdown of NUP98 caused severe chromosome segregation defects and disrupted RAE1 but not HDAC1 expression and localization. Next, we performed rescue experiments to confirm that the RAE1-NUP98 complex orchestrates proper chromosome segregation. Interestingly, we found diverse behaviors of NUP98 and the leukemogenic fusion protein NUP98-HOXA9 throughout the cell cycle. Strikingly, in NUP98-HOXA9-transfected cells, RAE1 protein were reduced and mis-localized. Our cellular interpretations were further confirmed by NUP98-HOXA9 transgenic mice and the NUP98-HOXA9 AML patient. These data suggest that RAE1 orchestrates NUP98-mediated leukemogenesis and raise the possibility that targeting this negative feedback loop may provide a new strategy for the therapy of aggressive leukemias.


Open Access Article

Cell cycle suspension: A novel process lurking in G₂ arrest

Jinpeng He, Junhong Li, Caiyong Ye, Libin Zhou, Jiayun Zhu, Jufang Wang, Atsushi Mizota, Yoshiya Furusawa and Guangming Zhou
Pages 1468 - 1476
http://dx.doi.org/10.4161/cc.10.9.15510
Abstract | PDF

Cell cycle checkpoint is a self-protective mechanism for cells to monitor genome integrity and ensure the high-fidelity transmission of genetic information to daughter cells. Insufficient function of cell cycle checkpoints has been demonstrated to partially account for tumor initiation, promotion and progression. In the ten melanoma cell lines that we tested in preliminary experiments, two human uveal melanoma cell lines, 92-1 and OCM-1, were found to be significantly different in terms of radiosensitivity but similar in DNA repair ability. Evident G₂ arrest was induced in both cell types and the maximum was reached at 16 h after irradiation regardless of X-rays or high-LET carbon beams. OCM-1 cells overrode the G₂ arrest and reentered the cell cycle right after reaching the maximum, whereas 92-1 could not. Upon 10 Gy of radiation, the cell cycle of 92-1 was suspended and remained unchanged for up to 5 d. The cell cycle suspension is a unique process lurking in G₂ arrest and related to cellular radiosensitivity. Its induction is dose-dependent and there is a dose threshold for it. The degradation of Cyclin B1 has been found related to the cell cycle suspension though, the mechanism of cell cycle suspension is still under investigation. Basing on our knowledge, this is the first report on cell cycle suspension and we present here a de novo mechanism to cellular radiosensitivity. Further clarification of the mechanism underlying cell cycle suspension is believed to be of significance in tumor radiosensitization or even direct tumor control.

Open Access Article

Identification and molecular characterization of the mammalian α-kleisin RAD21L

Cristina Gutiérrez-Caballero, Yurema Herrán, Manuel Sánchez-Martín, José Ángel Suja, José Luis Barbero, Elena Llano and Alberto M. Pendás
Pages 1477 - 1487
http://dx.doi.org/10.4161/cc.10.9.15515
Abstract | PDF

Meiosis is a fundamental process that generates new combinations between maternal and paternal genomes and haploid gametes from diploid progenitors. Many of the meiosis-specific events stem from the behavior of the cohesin complex (CC), a proteinaceous ring structure that entraps sister chromatids until the onset of anaphase. CCs ensure chromosome segregation, participate in DNA repair, regulate gene expression, and also contribute to synaptonemal complex (SC) formation at meiosis by keeping long-range distant DNA interactions through its conserved structure. Studies from yeast to humans have led to the assumption that Scc1/RAD21 is the α-kleisin that closes the tripartite CC that entraps two DNA molecules in mitosis, while its paralog REC8 is essential for meiosis. Here we describe the identification of RAD21L, a novel mammalian CC subunit with homology to the RAD21/REC8 α-kleisin subfamily, which is expressed in mouse testis. RAD21L interacts with other cohesin subunits such as SMC1α, SMC1b, SMC3 and with the meiosis-specific STAG3 protein. Thus, our results demonstrate the existence of a new meiotic-specific CC constituted by this α-kleisin and expand the view of REC8 as the only specific meiotic α-kleisin.

Open Access Article

Epigenetic regulation of Nanog expression by Ezh2 in pluripotent stem cells

Aranzazu Villasante, Daniela Piazzolla, Han Li, Gonzalo Gómez-López, Malek Djabali and Manuel Serrano
Pages 1488 - 1498
http://dx.doi.org/10.4161/cc.10.9.15658
Abstract | PDF

Nanog levels in pluripotent stem cells are heterogeneous and this is thought to reflect two different and interchangeable cell states, respectively poised to self-renew (Nanog-high subpopulation) or to differentiate (Nanog-low subpopulation). However, little is known about the mechanisms responsible for this pattern of Nanog expression. Here, we have examined the impact of the histone methyltransferase Ezh2 on pluripotent stem cells and on Nanog expression. Interestingly, induced pluripotent stem (iPS) cells lacking Ezh2 presented higher levels of Nanog due to a relative expansion of the Nanog-high subpopulation, and this was associated to severe defects in differentiation. Moreover, we found that the Nanog promoter in embryonic stem (ES) cells and iPS cells coexists in two alternative univalent chromatin configurations, either H3K4me3 or H3K27me3, the latter being dependent on the presence of functional Ezh2. Finally, the levels of expression of Ezh2, as well as the amount of H3K27me3 present at the Nanog promoter, were higher in the Nanog-low subpopulation of ES/iPS cells. Together, these data indicate that Ezh2 directly regulates the epigenetic status of the Nanog promoter affecting the balance of Nanog expression in pluripotent stem cells and, therefore, the equilibrium between self-renewal and differentiation.




LETTERS TO THE EDITOR

Open Access Article

Metformin activates an Ataxia Telangiectasia Mutated (ATM)/Chk2-regulated DNA damage-like response

Alejandro Vazquez-Martin, Cristina Oliveras-Ferraros, Sílvia Cufí, Begoña Martin-Castillo and Javier A. Menendez
Pages 1499 - 1501
http://dx.doi.org/10.4161/cc.10.9.15423
Abstract | PDF




Open Access Article

Clues for c-Yes involvement in the cell cycle and cytokinesis

Jessica Jung, Marie-Katrina Lee, Yan Jin, Song-bin Fu, Jesusa L. Rosales and Ki-Young Lee
Pages 1502 - 1503
http://dx.doi.org/10.4161/cc.10.9.15495
Abstract | PDF