Table of Contents

Volume 9, Issue 19

  October 1, 2010

  Pages 3831 - 4031

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EDITORIALS: CELL CYCLE FEATURES

Open Access Article

Activation of senescence and aging characteristics by mitochondrially generated ROS: How are they linked?

John Papaconstantinou and Ching-Chyuan Hsieh
Pages 3831 - 3833
http://dx.doi.org/10.4161/cc.9.19.13324
Abstract | PDF

This article discusses the molecular mechanism(s) that link oxidative stress (ROS) due to mitochondrial dysfunction to the activation of the ROS-sensitive signaling pathways whose levels of activity promote the development of senescence, aging, longevity, and resistance to oxidative stress. Most significantly, our discussion links ROS generated by mitochondrial dysfunction (ROS) to the activation of the ASK1-signalosome - p38 pathway. Our hypothesis argues that this is a major pathway that promotes physiological senescence, aging and age-associated diseases. We thus conclude that the ASK1-signalosome serves as an ROS-sensory system that regulates the levels of ROS-responsive p38 MAPK signals and serves as a signaling center that mediates the physiological consequences of mitochondrial dysfunction.

Open Access Article

Telomeres and inflammation: Rap1 joins the ends?

Arka Subhra Ghosh and Vinay Tergaonkar
Pages 3834 - 3835
http://dx.doi.org/10.4161/cc.9.19.13383
Abstract | PDF

Comment on: Teo H, et al. Nat Cell Biol. 2010; 12:758-67.

Open Access Article

Cross-talk between post-translational modifications regulates life or death decisions by E2F1

Haroula Kontaki and Iannis Talianidis
Pages 3836 - 3837
http://dx.doi.org/10.4161/cc.9.19.13384
Abstract | PDF

Comment on: Kontaki H, et al. Mol Cell. 2010; 39:152-60.

Open Access Article

NFAT transcription factors, the potion mediating "Dr. Jekyll-Mr. Hyde" transformation of the TGFβ pathway in cancer cells

Martin E. Fernandez-Zapico and Volker Ellenrieder
Pages 3838 - 3839
http://dx.doi.org/10.4161/cc.9.19.13413
Abstract | PDF

Feature on: Singh G, et al. J Biol Chem 2010; 285:27241–50.

Open Access Article

The genetic architecture of aging: Sexual antagonistic plieotropy of p53 and foxo

John Tower
Pages 3840 - 3841
http://dx.doi.org/10.4161/cc.9.19.13464
PDF




CELL CYCLE NEWS & VIEWS

Open Access Article

Building a great wall around mitosis: Evolutionary conserved roles for the Greatwall/MASTL kinases in securing chromosome stability

Małgorzata Krajewska and Marcel A.T.M. van Vugt
Pages 3842 - 3847
http://dx.doi.org/10.4161/cc.9.19.13282
Abstract | PDF

Comment on: Voets E, et al. Cell Cycle 2010; 9:3591–3601 & Burgess A, et al. Proc Natl Acad Sci USA 2010; 107:12564–9.

Open Access Article

Controlled chaos: New insights into genetically programmed cell cycle asynchrony

James Umen

http://dx.doi.org/10.4161/cc.9.19.13379
Abstract | PDF

Comment on: Nair DR, et al. Cell Cycle 2010; 9:3771–9.

Open Access Article

A swim in the same cytoplasm is no cure for nonconformity

Curt Wittenberg

http://dx.doi.org/10.4161/cc.9.19.13380
Abstract | PDF

Comment on: Nair DR, et al. Cell Cycle 2010; 9:3771–9.

Open Access Article

Deciphering the DNA damage histone code

Amy DeMicco and Craig H. Bassing

http://dx.doi.org/10.4161/cc.9.19.13381
Abstract | PDF

Comment on: Xie A, et al. Cell Cycle 2010; 9:3602–10.

Open Access Article

ING2 in cell cycle regulation

Gang Li and Brad Piche

http://dx.doi.org/10.4161/cc.9.19.13382
Abstract | PDF

Comment on: Larrieu D, et al. Cell Cycle 2010; 9:2984–90.

Open Access Article

A dynamic methylome: Implications of non-CG methylation/demethylation

Moshe Szyf

http://dx.doi.org/10.4161/cc.9.19.13563
Abstract | PDF

Comment on: Fuso A, et al. Cell Cycle 2010; 9:3965–76.




FEATURE SERIES: BIOSCIENCE AROUND THE GLOBE

Open Access Article

In focus: Georgia

Yelena Boryskina
Pages 3848 - 3850
http://dx.doi.org/10.4161/cc.9.19.13409
Abstract | PDF

Georgia is situated in the Caucasus region where Eastern Europe and Western Asia meet. The country covers a territory of 69,700 km² and its population is 4.385 million people. Formerly a part of the Soviet Union, Georgia restored its independence in 1991. Since then the country has struggled to renovate its economical and political structure, while saving the best from the past and exploring new opportunities. Bioscience is an essential part of this process. We have interviewed several leading Georgian scientists and asked them to describe the problems and accomplishments in their areas of bioscience.




EXTRA VIEWS

Open Access Article

The dark side of fly TNF: An ancient developmental proof reading mechanism turned into tumor promoter

Marcos Vidal
Pages 3851 - 3856
http://dx.doi.org/10.4161/cc.9.19.13280
Abstract | PDF

The fruit fly Drosophila is an important model for biological research; however, due to its relatively short lifespan its relevance in cancer research is often questioned.  Nevertheless, among many other intriguing Drosophila models, scribble group mutants provided early evidence for the existence of tumour suppressor genes and their importance in mammalian systems is beginning to emerge. In this review, I discuss recent advances in our understanding of the phenotypes of scrib group gene mutants, in which the activation of JNK signaling plays a crucial role. Several mechanisms can account for the activation of JNK within scrib group mutant cells, including a mechanical stress triggered by the loss of polarity, cell competition, intrinsic tumour suppression by autonomous production of Eiger, and an inflammatory response mediated by Eiger-producing haemocytes. Eiger, the sole Drosophila homolog of tumour necrosis factor, is emerging as a 'danger signal' initiated upon the presence of external pathogens, damaged tissues, and the appearance of pre-malignant cells. Remarkably, in the presence of the Ras oncoprotein Eiger can act as a tumor promoter by stimulating invasive migration and delaying the onset of metamorphosis.

Open Access Article

Coordinate regulation of histone mRNA metabolism and DNA replication: Cyclin A/cdk1 is involved in inactivation of histone mRNA metabolism and DNA replication at the end of S phase

M. Murat Koseoglu, Jian Dong and William F. Marzluff
Pages 3857 - 3863
http://dx.doi.org/10.4161/cc.9.19.13300
Abstract | PDF

S phase is characterized by the replication of DNA and assembly of chromatin.  This requires the synthesis of large amounts of histone proteins to package the newly replicated DNA.  Histone mRNAs are the only mRNAs that do not have polyA tails, ending instead in a conserved stemloop sequence.  The stemloop binding protein (SLBP) that binds the 3' end of histone mRNA is cell cycle regulated and SLBP is required in all steps of histone mRNA metabolism.  Activation of cyclin E/cdk2 prior to entry into S phase is critical for initiation of DNA replication and histone mRNA accumulation.  At the end of S phase SLBP is rapidly degraded as a result of phosphorylation of SLBP by cyclin A/cdk1 and CK2 effectively shutting off histone mRNA biosynthesis.  E2F1, which is required for expression of many S-phase genes, is regulated in parallel with SLBP and its degradation also requires a cyclin binding site, suggesting that it may also be regulated by the same pathway.  It is likely that activation of cyclin A/cdk1 so helps inhibit both DNA replication and histone mRNA accumulation, marking the end of S phase and entry into G2 phase.

Open Access Article

Circadian clocks and cell division: What's the pacemaker?

Carl Hirschie Johnson
Pages 3864 - 3873
http://dx.doi.org/10.4161/cc.9.19.13205
Abstract | PDF

Evolution has selected a system of two intertwined cell cycles: the cell division cycle (CDC) and the daily (circadian) biological clock. The circadian clock keeps track of solar time and programs biological processes to occur at environmentally appropriate times. One of these processes is the CDC, which is often gated by the circadian clock. The intermeshing of these two cell cycles is probably responsible for the observation that disruption of the circadian system enhances susceptibility to some kinds of cancer. The core mechanism underlying the circadian clockwork has been thought to be a transcription & translation feedback loop (TTFL), but recent evidence from studies with cyanobacteria, synthetic oscillators, and immortalized cell lines suggests that the core circadian pacemaking mechanism that gates cell division in mammalian cells could be a post-translational oscillator (PTO).

Open Access Article

Spinal muscular atrophy: A new player joins the battle for SMN2 exon 7 splicing

Simona Pedrotti and Claudio Sette
Pages 3874 - 3879
http://dx.doi.org/10.4161/cc.9.19.13153
Abstract | PDF

Spinal Muscular Atrophy (SMA) is a neurodegenerative disease with high impact in the human population, being the leading genetic cause of death in infancy. No cure is currently available for SMA, raising interest in the development of novel therapeutic strategies for this disease. Much of the effort in this sense has been aimed at increasing the SMN2-derived transcript levels, either by improving transcription rate or by reprogramming exon 7 splicing. Herein, we discuss recent findings on the regulation of SMN2 gene expression, focusing on splicing modulation as a therapeutic target. We review the literature regarding splicing factors involved in the regulation of exon 7 splicing in SMN2, and discuss the role played in this process by the RNA binding protein Sam68, a novel crucial regulator of SMN2 splicing.

Open Access Article

DNA methylation and epigenetic control of cellular differentiation

David A. Khavari, George L. Sen and John L. Rinn
Pages 3880 - 3883
http://dx.doi.org/10.4161/cc.9.19.13385
Abstract | PDF

In mammals the genome is shaped by epigenetic regulation to manifest numerous cellular identities. The term epigenetics has been used to refer to changes in gene expression, which are heritable through multiple cell division cycles that are not due to variations in primary DNA sequence.^1-3 Stable suppression of differentiation genes is required to sustain the undifferentiated state in cells ranging from embryonic stem cells to somatic stem cell progenitors that constantly replenish self-renewing tissues. However, the epigenetic mechanisms behind the maintenance of cellular dedifferentiation are not yet fully understood. Major effectors of epigenetic control include regulators of DNA methylation and histone modification as well as ATP-dependent chromatin remodeling enzymes. These interact with other regulators, such as DNA sequence-specific transcription factors and noncoding RNAs to landscape the genome during development, differentiation and cancer. DNA methylation is a classic and powerful example of the epigenetic inheritance of cellular identity that is widely used in eukaryotes.⁴ DNA methylation confers distinct epigenetic states via several mechanisms.^{5, 6} Here we discuss fundamental mechanisms of DNA methylation and their interplay with several regulatory pathways that define cellular physiology and differentiation.




PERSPECTIVE

Open Access Article

Glutaminolysis: Supplying carbon or nitrogen or both for cancer cells?

Chi V. Dang
Pages 3884 - 3886
http://dx.doi.org/10.4161/cc.9.19.13302
Abstract | PDF

A cancer cell comprising largely of carbon, hydrogen, oxygen, phosphorus, nitrogen and sulfur requires not only glucose, which is avidly transported and converted to lactate by aerobic glycolysis or the Warburg effect, but also glutamine as a major substrate.  Glutamine and essential amino acids, such as methionine, provide energy through the TCA cycle as well as nitrogen, sulfur and carbon skeletons for growing and proliferating cancer cells.  The interplay between utilization of glutamine and glucose is likely to depend on the genetic make-up of a cancer cell.  While the MYC oncogene induces both aerobic glycolysis and glutaminolysis, activated b-catenin induces glutamine synthesis in hepatocellular carcinoma.  Cancer cells that have elevated glutamine synthetase can use glutamate and ammonia to synthesize glutamine and are hence not addicted to glutamine.  As such, cancer cells have many degrees of freedom for re-programming cell metabolism, which with better understanding will result in novel therapeutic approaches.




REVIEWS

Open Access Article

p53: Guardian of reprogramming

Sergio Menendez, Suzanne Camus and Juan Carlos Izpisua Belmonte
Pages 3887 - 3891
http://dx.doi.org/10.4161/cc.9.19.13301
Abstract | PDF

The reprogramming of somatic cells to induced pluripotent stem (iPS) cells is one of the major discoveries of recent years. The development and application of patient specific iPS lines could potentially revolutionize cell-based therapy, facilitating the treatment of a wide range of diseases.  Despite the numerous technological advancements in the field, an in-depth mechanistical understanding of the pathways involved in reprogramming is still lacking. Several groups have recently provided a mechanistical insight into the role of the p53 tumor suppressor pathway in reprogramming. The repercussions of these findings are profound and reveal an unexpected role of p53 as a "guardian of reprogramming", ensuring genomic integrity during reprogramming at the cost of a reduced efficiency of the process. Here we analyze the latest findings in the field and discuss their relevance for future applications of iPS cell technology.

Open Access Article

LATS tumor suppressor: A new governor of cellular homeostasis

Stacy Visser and Xiaolong Yang
Pages 3892 - 3903
http://dx.doi.org/10.4161/cc.9.19.13386
Abstract | PDF

Accumulating evidence points to the LATS (Large Tumor Suppressor) family of human tumor suppressors (LATS1 and LATS2) as new resident governors of cellular homeostasis.  Loss of function of either LATS1 or LATS2 leads to a variety of tumor types including soft tissue sarcomas, leukemia, as well as breast, prostate, lung, and esophageal cancers.  Due to their high degree of homology and functional overlap, LATS1 and LATS2 comprise a new tumor suppressor family.  Classically identified within the Hippo-LATS signaling pathway, LATS also acts independently of this pathway, possessing multiple functions including regulation of cell proliferation, cell death, and cell migration, as well as broad governing roles such as transcriptional regulation and maintenance of genetic stability.  Activity of LATS is tightly controlled through various mechanisms including post-translational modifications, differential localization and expression.  Although little is known about the specific underlying mechanisms of these activities, current data suggest that LATS signaling intersects with well-established tumor suppressive or oncogenic pathways including the p53, Ras, or Akt networks.  This review aims to identify what we know about the LATS tumor suppressor family, highlighting LATS1 and LATS2 redundancies or differences in terms of their structure, expression, regulation, and functions, thereby establishing a novel tumor suppressor network.

Open Access Article

APC/C-Cdh1: From cell cycle to cellular differentiation and genomic integrity

Xinxian Qiao, Liyong Zhang, Armin M. Gamper, Takeo Fujita and Yong Wan
Pages 3904 - 3912
http://dx.doi.org/10.4161/cc.9.19.13585
Abstract | PDF

Anaphase-promoting complex/cyclosome (APC/C) is a multifunctional ubiquitin-protein ligase that targets various substrates for proteolysis inside and outside of cell cycle. The activation of APC/C is depended on two WD-40 domain proteins, Cdc20 and Cdh1. While APC/Cdc20 principally regulates mitotic progression, APC/Cdh1 shows a broad spectrum of substrates in and beyond cell cycle. In past several years, numerous biochemical and mouse genetic studies have greatly attracted our attention to the emerging role of APC/Cdh1 in genomic integrity, cellular differentiation and human diseases. This review will aim to summarize the recent expended understanding of APC/Cdh1 in regulating biological function and how its dysfunction may lead to diseases.




REPORTS

Open Access Article

Regulation of the ATM-activator protein Aven by CRM1-dependent nuclear export

Armond M. Esmaili, Erika L. Johnson, Silpa S. Thaivalappil, Helena M. Kuhn, Sally Kornbluth and Pablo M. Irusta
Pages 3913 - 3920
http://dx.doi.org/10.4161/cc.9.19.13138
Abstract | PDF

Aven is a regulator of apoptosis whose overexpression is associated with poor prognosis in several cancers, including childhood acute lymphoblastic leukemia and acute myeloid leukemia. We have recently shown that Aven serves as an activator and substrate of ATM, thereby modulating the DNA-damage response and G2/M cell cycle progression. Under physiological conditions, the cellular localization of Aven is mainly cytosolic, but a small fraction of the protein is present in the nucleus. Here, we show that treatment of cells with leptomycin B, an inhibitor of Exportin-1/CRM (chromosomal region maintenance) 1, resulted in nuclear accumulation of Aven. Furthermore, we identified a functional LR-NES between amino acid residues 282-292 of the human Aven protein, a sequence that is evolutionary conserved among a range of vertebrate species. Disruption of this LR-NES by site-directed mutagenesis resulted in enhanced nuclear localization of Aven, but did not alter the ability of the protein to induce G2/M cell cycle arrest in interphase Xenopus laevis extracts. However, elimination of the LR-NES sequence led to a reduction in the capacity of Aven to arrest Xenopus oocytes containing intact nuclei. Our results suggest that the regulation of nucleocytoplasmatic traffic of Aven could modulate its ability to influence cell cycle progression.

Open Access Article

Nitrogen anabolism underlies the importance of glutaminolysis in proliferating cells

Meng Meng, Shuyang Chen, Taotao Lao, Dongming Liang and Nianli Sang
Pages 3921 - 3932
http://dx.doi.org/10.4161/cc.9.19.13139
Abstract | PDF

Warburg effect and glutaminolysis are the two most noticeable metabolic features of tumor cells. A recent hypothesis is that tumor cells use glutamine as a preferred carbon source for energy and reducing power, which has been used to explain both Warburg effect and glutaminolysis. Here we provide evidence to demonstrate that supplying nitrogen, not the carbon skeleton, underlies the biological importance of glutaminolysis for proliferating cells. We show alternative nitrogen supplying mechanisms rescue Hep3B and HeLa cell proliferation in glutamine-free media. We conclude that cellular demand for nitrogen is a driving force of glutaminolysis for proliferating cells, and propose that glutamine addiction and Warburg effect are metabolic consequences of coordinated utilization of nitrogen and carbon sources for biosynthesis.

Open Access Article

Oct1 is required for mTOR-induced G₁ cell cycle arrest via the control of p27^Kip1 expression

Mathieu Dalvai, Karin Schubart, Arnaud Besson and Patrick Matthias
Pages 3933 - 3944
http://dx.doi.org/10.4161/cc.9.19.13154
Abstract | PDF

Oct1 is a ubiquitously expressed transcription factor that is induced in response to DNA damage to modulate gene expression. Herein, Oct1 deficient mouse embryonic fibroblasts were used as a model to study the importance of Oct1 in cellular stress response. Cells lacking Oct1 kept proliferating and bypassed the G1 cell cycle arrest induced by glucose or amino acid starvation. Indeed, mTOR-mediated regulation of proliferation was abolished in Oct1^-/- cells starved for glucose or amino acids and Oct1^-/- cells were also insensitive to mTOR inhibition by rapamycin. Furthermore, in wild-type cells, Oct1 controls the transcription of the CDK inhibitor p27^Kip1 downstream of the mTOR pathway and Oct1-null cells failed to upregulate p27^Kip1 in response to rapamycin or glucose starvation. p27^Kip1 is required for rapamycin or nutrient starvation-induced G1-arrest, as p27^-/- fibroblasts were largely insensitive to rapamycin treatment or glucose starvation. Thus, Oct1 appears to be a critical mediator of the growth arrest induced by mTOR inhibition via the control of p27^Kip1 expression.

Open Access Article

p21^Waf1 is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate

Vasily S. Romanov, Maria V. Abramova, Svetlana B. Svetlikova, Tatiana V. Bykova, Svetlana G. Zubova, Nikolai D. Aksenov, Albert J. Fornace, Tatiana V. Pospelova and Valery A. Pospelov
Pages 3945 - 3955
http://dx.doi.org/10.4161/cc.9.19.13160
Abstract | PDF

Cell senescence is characterized by senescent morphology and permanent loss of proliferative potential. HDAC inhibitors (HDACI) induce senescence and/or apoptosis in many types of tumor cells. Here, we studied the role of cyclin-kinase inhibitor p21^waf1(Cdkn1n gene) in cell cycle arrest,   senescence markers (cell hypertrophy, SA-bGal staining and accumulation of gH2AX foci) in p21^Waf1+/+ versus p21^Waf1-/- mouse embryonic fibroblast cells transformed with E1A and cHa-Ras oncogenes (mERas). While short treatment with the HDACI sodium butyrate (NaB) induced a reversible G1 cell cycle arrest in both parental and p21^Waf1-/- cells, long-term treatment led to dramatic changes in p21^Waf1+/+ cells only: cell cycle arrest became irreversible and cells become hypertrophic,  SA-bGal-positive and accumulated gH2AX foci associated with mTORC1 activation. The p21^Waf1+/+ cells lost their ability to migrate into the wound and through a porous membrane. Suppression of migration was accompanied by accumulation of vinculin-staining focal adhesions and Ser3-phosphorylation of cofilin, incapable for F-actin depolymerization. In contrast, the knockout of the p21^Waf1 abolished most of the features of NaB-induced senescence, including irreversibility of cell cycle arrest, hypertrophy, additional focal adhesions and block of migration, gH2AX foci accumulation and SA-bGal staining. Rapamycin, a specific inhibitor of mTORC1 kinase, decreased cellular hypertrophy, canceled coffilin phosphorylation and partially  restored cell migration in p21^Waf1+/+ cells. Taken together, our data indicate a new role of p21^Waf1 in cell senescence, which may be connected not with execution of cell cycle arrest, but also with the development of mTOR-dependent markers of cellular senescence.

Open Access Article

APC/C^Cdc20 targets E2F1 for degradation in prometaphase

Melissa J. Peart, Masha V. Poyurovsky, Elizabeth M. Kass, Marshall Urist, Emmy Verschuren, Matthew K. Summers, Peter K. Jackson and Carol Prives
Pages 3956 - 3964
http://dx.doi.org/10.4161/cc.9.19.13162
Abstract | PDF

The mechanisms that control E2F-1 activity are complex. We previously showed that Chk1 and Chk2 are required for E2F1 stabilization and p73 target gene induction following DNA damage. To gain further insight into the processes regulating E2F1 protein stability, we focused our investigation on the mechanisms responsible for regulating E2F1 turnover. Here we show that E2F1 is a substrate of the anaphase promoting complex or cyclosome (APC/C), a ubiquitin ligase that plays an important role in cell cycle progression. Ectopic expression of the APC/C activators Cdh1 and Cdc20 reduced the levels of co-expressed E2F-1 protein. Co-expression of DP1 with E2F1 blocked APC/C-induced E2F1 degradation, suggesting that the E2F1/DP1 heterodimer is protected from APC/C regulation. Following Cdc20 knockdown, E2F1 levels increased and remained stable in extracts over a time course, indicating that APC/C^Cdc20 is a primary regulator of E2F1 stability in vivo. Moreover, cell synchronization experiments showed that siRNA directed against Cdc20 induced an accumulation of E2F1 protein in prometaphase cells. These data suggest that APC/C^Cdc20 specifically targets E2F1 for degradation in early mitosis and reveal a novel mechanism for limiting free E2F1 levels in cells, failure of which may compromise cell survival and/or homeostasis.

Open Access Article

Early demethylation of non-CpG, CpC-rich, elements in the myogenin 5’-flanking region: A priming effect on the spreading of active demethylation?

Andrea Fuso, Giampiero Ferraguti, Francesco Grandoni, Raffaella Ruggeri, Sigfrido Scarpa, Roberto Strom and Marco Lucarelli
Pages 3965 - 3976
http://dx.doi.org/10.4161/cc.9.19.13193
Abstract | PDF

The dynamic changes and structural patterns of DNA methylation of genes without CpG islands are poorly characterized. The relevance of CpG to the non-CpG methylation equilibrium in transcriptional repression is unknown. In this work, we analyzed the DNA methylation pattern of the 5’-flanking of the myogenin gene, a positive regulator of muscle differentiation with no CpG island and low CpG density, in both C2C12 muscle satellite cells and embryonic muscle. Embryonic brain was studied as a non-expressing tissue. High levels of both CpG and non-CpG methylation were observed in non-expressing experimental conditions. Both CpG and non-CpG methylation rapidly dropped during muscle differentiation and myogenin transcriptional activation, with an active demethylation dynamics. Non-CpG demethylation occurred more rapidly than CpG demethylation. Demethylation spread from initially highly methylated short CpC-rich elements to a virtually unmethylated status. These short elements have a high CpC content and density, share some motifs and largely coincide with putative recognition sequences of some differentiation-related transcription factors. Our findings point to a dynamically controlled equilibrium between CpG and non-CpG active demethylation in the transcriptional control of tissue-specific genes. The short CpC-rich elements are new structural features of the methylation machinery, whose functions may include priming the complete demethylation of a transcriptionally crucial DNA region.

Open Access Article

Human KIAA1018/FAN1 localizes to stalled replication forks via its ubiquitin-binding domain

Robert D. Shereda, Yuka Machida and Yuichi J. Machida
Pages 3977 - 3983
http://dx.doi.org/10.4161/cc.9.19.13207
Abstract | PDF

Genome maintenance pathways correct aberrations in DNA that would be deleterious to the organism.  A crucial element of many genome maintenance processes is the ability to degrade DNA that either contains errors or obscures useful substrates for recombination and/or repair by means of nucleases.  We have examined a putative nuclease that has heretofore been unreported, KIAA1018/FAN1.  This protein contains a predicted ubiquitin-binding zinc finger domain (UBZ) near its N-terminus and an endonuclease-like fold near its C-terminus.  Here we describe that FAN1 is a nuclear protein and forms DNA-damage-induced foci, which appear to be at stalled replication forks as denoted by RPA colocalization.  Localization of FAN1 to sites of damage is dependent upon its UBZ domain.  In addition, knockdown of FAN1 by RNA interference leads to increased sensitivity to interstrand crosslinking agents and accumulation of abnormal chromosomes.  FAN1 may be an important new player in the maintenance of genome stability.

Open Access Article

ING2 controls the G₁ to S-phase transition by regulating p21 expression

Delphine Larrieu, Damien Ythier, Christian Brambilla and Rémy Pedeux
Pages 3984 - 3990
http://dx.doi.org/10.4161/cc.9.19.13208
Abstract | PDF

ING2 (Inhibitor of Growth 2) is a candidate tumor suppressive protein frequently lost in human tumors. Recently, we have reported that ING2 downregulation impairs DNA replication forks progression and leads to genome instability. To better understand the tumor suppressive functions of ING2 and its role in the cell cycle, we downregulated its expression in cells and studied the consequences of this downregulation on the G1/S transition. We observed that the inhibition of ING2 expression accelerated the progression of cells from G1 to S phase, and was accompanied by a decrease of p21 expression. Moreover, we show that the regulation of p21 by ING2 is independent, of the tumor suppressive protein p53. Interestingly, this function seems to be unique for ING2 since its closest homologue ING1 does not regulate the G1/S transition. It has been suggested previously that ING2 may modulate the trimethylation of H3K4 at the promoter of p21. Accordingly, our results suggest that there may be a link between the regulation of the G1/S transition by ING2 and the level of H3K4Me3. All together, these results bring new information concerning the role of ING2 in the regulation of the cell cycle and suggest that it may play important roles in controlling several S phase checkpoints.

Open Access Article

Yeast lsm pro-apoptotic mutants show defects in S-phase entry and progression

Vanessa Palermo, Enrico Cundari, Eleonora Mangiapelo, Claudio Falcone and Cristina Mazzoni
Pages 3991 - 3996
http://dx.doi.org/10.4161/cc.9.19.13210
Abstract | PDF

Expression of the histone genes is tightly coupled to rates of DNA synthesis in yeast and histone mRNAs are modulated both transcriptionally and post-transcriptionally. Trf4 and Trf5, poly(A) polymerases, that mediates polyadenylation and consequent degradation) and Rrp6, an exosome component, play a role in the regulation of histone mRNA levels. In this paper we show that in the mRNA degradation mutant Kllsm4D1, histone mRNAs are induced early in the S-phase and maintained at high level all along the entire cell cycle due to a delay in the exit from S-phase and/or entry into M-phase. The over-expression of the HIR1 gene (Histone transcriptional repressor), previously isolated as a multicopy suppressor of the apoptotic phenotypes observed in Kllsm4D1, can also restore the normal cycling of histone genes expression. We also found that low doses of hydroxyurea neutralize the onset of the apoptotic phenotypes in Kllsm4D1, as well in another mRNA decapping mutants (lsm1) and, in addition, increase the chronological lifespan in both strains suggesting that an entry delay into the S phase can recover some cellular defects in decapping mutants.

Open Access Article

Laser microsurgery provides evidence for merotelic kinetochore attachments in fission yeast cells lacking Pcs1 or Clr4

Cornelia Rumpf, Lubos Cipak, Alexander Schleiffer, Alison Pidoux, Karl Mechtler, Iva M. Tolić-Nørrelykke and Juraj Gregan
Pages 3997 - 4004
http://dx.doi.org/10.4161/cc.9.19.13233
Abstract | PDF

In order to segregate chromosomes properly, the cell must prevent merotelic kinetochore attachment, an error that occurs when a single kinetochore is attached to microtubules emanating from both spindle poles. Merotelic kinetochore orientation represents a major mechanism of aneuploidy in mitotic mammalian cells and it is the primary mechanism of chromosome instability in cancer cells. Fission yeast mutants defective in putative microtubule-site clamp Pcs1/Mde4 or Clr4/Swi6-dependent centromeric heterochromatin display high frequencies of lagging chromosomes during anaphase. Here, we developed an assay based on laser microsurgery to show that the stretched morphology of lagging kinetochores in pcs1Δ and clr4Δ mutant cells is due to merotelic attachment. We further show that Mde4 is regulated by Cdc2 and that Cdc2 activity prevents precocious localization of Mde4 to the metaphase spindle. Finally, we show that Pcs1/Mde4 complex shares similar features with the conserved kinetochore complex Spc24/Spc25 suggesting that these two complexes may occupy a similar functional niche.

Open Access Article

Depletion of ribosomal protein L37 occurs in response to DNA damage and activates p53 through the L11/MDM2 pathway

Susana Llanos and Manuel Serrano
Pages 4005 - 4012
http://dx.doi.org/10.4161/cc.9.19.13299
Abstract | PDF

Perturbation of ribosomal biogenesis has recently emerged as a relevant p53-activating pathway. This pathway can be initiated by depletion of certain ribosomal proteins, which is followed by the binding and inhibition of MDM2 with a different subset of ribosomal proteins that includes L11. Here, we report that depletion of L37 leads to cell cycle arrest in a L11- and p53-dependent manner. DNA damage can initiate ribosomal stress, although little is known about the mechanisms involved. We have found that some genotoxic insults, namely, UV light and cisplatin, lead to proteasomal degradation of L37 in the nucleoplasm and to the ensuing L11-dependent stabilization of p53. Moreover, ectopic L37 overexpression can attenuate the DNA damage response mediated by p53. These results support the concept that DNA damage-induced proteasomal degradation of L37 can constitute a mechanistic link between DNA damage and the ribosomal stress pathway, and a relevant contributing signaling pathway for the activation of p53 in response to DNA damage.

Open Access Article

β-Arrestin-1 links mitogenic sonic hedgehog signaling to the cell cycle exit machinery in neural precursors

Susana R. Parathath, Lori Anne Mainwaring, Africa Fernandez-L, Cemile G. Guldal, Zaher Nahlé and Anna M. Kenney
Pages 4013 - 4024
http://dx.doi.org/10.4161/cc.9.19.13325
Abstract | PDF

Development of the cerebellum, a brain region regulating posture and coordination, occurs post-natally and is marked by rapid proliferation of granule neuron precursors (CGNPs), stimulated by mitogenic Sonic hedgehog (Shh) signaling. β-Arrestin (βArr) proteins play important roles downstream of Smoothened, the Shh signal transducer. However, whether Shh regulates βArrs and what role they play in Shh-driven CGNP proliferation remains to be determined. Here, we report that Shh induces βArr1 accumulation and localization to the nucleus, where it participates in enhancing expression of the cyclin dependent kinase (cdk) inhibitor p27, whose accumulation eventually drives CGNP cell cycle exit. βArr1 knock-down enhances CGNP proliferation and reduces p27 expression. Thus, Shh-mediated βArr1 induction represents a novel negative feedback loop within the Shh mitogenic pathway, such that ongoing Shh signaling, while required for CGNPs to proliferate, also sets up a cell-intrinsic clock programming their ultimate exit from the cell cycle.




LETTERS TO THE EDITOR

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The CINSARC signature: Prognostic and predictive of response to chemotherapy?

François Bertucci, Pascal Finetti, Renaud Sabatier and Daniel Birnbaum
Pages 4025 - 4027
http://dx.doi.org/10.4161/cc.9.19.13463
PDF

Open Access Article

Differential basal levels of MDM-2 transcription induced by p53-P72 and p53-R72

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Pages 4028 - 4030
http://dx.doi.org/10.4161/cc.9.19.13467
PDF




ERRATUM

Open Access Article

Crystallization of eIF4E complexed with eIF4GI peptide and glycerol reveals distinct structural differences around the cap-binding site

Christopher John Brown, Chandra S. Verma, Malcolm D. Walkinshaw and David P. Lane
Page 4031
http://dx.doi.org/10.4161/cc.9.19.13769
Abstract | PDF

It has come to our attention that there is an error in the chemical formula for NH₄SO₄ throughout our previously published manuscript, Brown CJ, et al. Cell Cycle 2009; 8:1905-1911. This should be (NH₄)₂SO₄. We sincerely regret these errors and any confusion they may cause.