Table of Contents

Volume 5, Issue 10

  May 15, 2006

  Pages 1015 - 1124

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 Issue Catalogue (MARC XML)

CUTTING EDGE VIEWS

Open Access Article

Micro or Mega: How Important are microRNAs in Muscle?

Da-Zhi Wang
Pages 1015 - 1016
http://dx.doi.org/10.4161/cc.5.10.2742
Abstract | PDF

No abstract available.




EXTRA VIEWS

Open Access Article

Glucocorticoid-Induced Apoptosis: Revisited: A Novel Role for Glucocorticoid Receptor Translocation to the Mitochondria

Ronit Vogt Sionov, Shlomit Kfir, Elazar Zafrir, Orly Cohen, Yael Zilberman and Eitan Yefenof
Pages 1017 - 1026
http://dx.doi.org/10.4161/cc.5.10.2738
Abstract | PDF

Recent data cast new light on the mechanisms by which glucocorticoids (GCs) elicit apoptosis of thymocytes and leukemia cells. Here we attempt to integrate recent studies by others and us, which provide a novel insight to this apoptotic process. In the last few years it was made clear that there is a tight cooperation between genomic and non-genomic effects exerted by GC receptors (GRs). GC invokes major alterations in the gene expression profile through GR-mediated transactivation and transrepression, which ultimately tip the balance between pro-survival and pro-apoptotic proteins. Although essential in shaping the cell’s proteome, these genomic effects are insufficient to elicit apoptotic death and additional signals are required for activating the pro-apoptotic proteins. Several non-genomic effects have been described that occur immediately following exposure to GC, which are imperative for the induction of apoptosis. We have recently observed that GC induces instant GR translocation to the mitochondria in GCsensitive, but not in GC-resistant, T lymphoid cells. This response contrasts the nuclear translocation of GR occurring in both cell types. We propose that the sustained elevation of GR in the mitochondria following GC exposure is crucial for triggering apoptosis.

Open Access Article

Resveratrol and the Pharmacology of Aging: A New Vertebrate Model to Validate an Old Molecule

Dario Riccardo Valenzano and Alessandro Cellerino
Pages 1027 - 1032
http://dx.doi.org/10.4161/cc.5.10.2739
Abstract | PDF

The natural phytoalexin resveratrol, found in grapes and red wine, recently raised to public fame for its positive effects on longevity in yeasts, worms and flies. Resveratrol anti-cancer and anti-inflammatory in vitro action on mammalian cell cultures also suggest a possible positive effect on human health and life-expectancy. To study the effects of resveratrol on vertebrate aging is obviously a particularly relevant question. We have studied resveratrol effects in a very short-lived vertebrate: the annual fish Nothobranchius furzeri. Resveratrol treatment prolonged lifespan and delayed the onset of age-related dysfunctions in this fish. This result identifies resveratrol as the first molecule which consistently retards aging in organisms as diverse as yeast, worm, fly and fish, but it also reveals the potential of this short-lived fish as an animal model for pharmacological research. Moreover, being related to stickleback (Gasterosteus aculeatus) the “pufferfishes” Takifugu and Tetraodon, and even more closely related to medaka (Oryzias latipes), it can greatly beneficiate from the recent development of genomic resources for these fish models and in the future become a complete model system for the aging research community.

Open Access Article

Visualizing the Behavior of Human Rad51 at the Single-Molecule Level

Caitlyn C. Yeykal and Eric C. Greene
Pages 1033 - 1038
http://dx.doi.org/10.4161/cc.5.10.2760
Abstract | PDF

The repair of double-stranded DNA breaks by homologous recombination is essential for maintaining genome integrity. Much of what we know about this DNA repair pathway in eukaryotes has been gleaned from genetics, in vivo experiments with GFP-tagged proteins and traditional biochemical experiments with purified proteins. However, many questions have remained inaccessible to these experimental approaches. Recent technological advances have made it possible to directly visualize the behaviors of individual DNA and protein molecules in vitro, and it is now becoming feasible to apply these technology-driven approaches to complex biochemical systems, such as those involved in the repair of damaged DNA. This report summarizes the use of total internal reflection fluorescence microscopy to probe fundamental aspects of protein-DNA interactions at the single-molecule level, and specific emphasis is placed on our efforts to develop new methods and techniques for studying DNA repair. Using these new approaches we are investigating the DNA-binding behavior of human Rad51 and we have recently demonstrated that this protein can slide on dsDNA via a one-dimensional random walk mechanism driven solely by thermal fluctuations of the surrounding solvent. Here, we highlight some possible implications of this recent finding, and we also briefly discuss the potential benefits of future single-molecule studies in the study of protein-DNA interactions and DNA repair.

Open Access Article

Spreading the Signal: Dissociation of Chk1 from Chromatin

Veronique A.J. Smits
Pages 1039 - 1043
http://dx.doi.org/10.4161/cc.5.10.2761
Abstract | PDF

The effector kinase Chk1 plays a critical role in the DNA damage checkpoint response by phosphorylating regulators of the cell cycle machinery, resulting in an inhibition of cell cycle progression. In the presence of genotoxic stress, the PI3 kinase-like kinase ATR rapidly phosphorylates Chk1 on conserved serine residues, thereby triggering kinase activation through the release of an auto-inhibitory region present at its C-terminus and by regulating interactions with other proteins. Recent data have demonstrated an additional regulatory mechanism of Chk1 functioning: Chk1 binds chromatin in unperturbed cells and dissociates from chromatin in response to DNA damage in a manner that is dependent on PIKK-mediated phosphorylation. Here, I give an overview of these findings and discuss the implications of these data for our understanding of the execution of the checkpoint arrest induced after the detection of DNA damage.

Open Access Article

DNA Interstrand Cross-Link Repair in the Cell Cycle: A Critical Role for Polymerase ζ in G₁ Phase

Peter J. McHugh and Sovan Sarkar
Pages 1044 - 1047
http://dx.doi.org/10.4161/cc.5.10.2763
Abstract | PDF

DNA interstrand cross-links (ICLs) present a formidable challenge to the cellular repair apparatus, but to date ICL repair pathways have proved difficult to dissect genetically. It now appears that this is partly the result of a high degree of cell cycle phase selectivity in the choice of ICL pathway employed. Here we review recent results showing that Polymerase ζ, aspecialised translesion polymerase, plays an important role during ICL repair in G₁ phase yeast cells, and that PCNA modification by ubiquitin is a key regulator of its activity. Given that this reaction can occur outside the context of S-phase, these results imply a more general role for PCNA modification in the control of DNA repair pathways through the cell cycle, which is dependent on the type of damage or repair intermediate encountered.

Open Access Article

Kaposi’s Sarcoma-Associated Herpesvirus LANA Hitches a Ride on the Chromosome

Andrew J. Barbera, Jayanth V. Chodaparambil, Brenna Kelley-Clarke, Karolin Luger and Kenneth M. Kaye
Pages 1048 - 1052
http://dx.doi.org/10.4161/cc.5.10.2768
Abstract | PDF

Kaposi’s sarcoma-associated herpesvirus (KSHV) latently infects tumor cells and has an etiologic role in Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease. Survival in rapidly dividing cells depends on a carefully orchestrated chain of events. The viral genome, or episome, must replicate in concert with cellular genetic material, and then efficiently segregate to progeny nuclei. KSHV achieves this through its latency associated nuclear antigen (LANA), which simultaneously binds to viral DNA and mitotic chromosomes to efficiently partition episomes. LANA’s N-terminal region has been shown to be essential for efficient KSHV DNA replication and tethering to mitotic chromosomes. The precise mechanism by which LANA attaches to host chromosomes has been an area of active investigation. We recently reported that this association is mediated by the chromatin components histones H2A and H2B. Binding between LANA and these proteins was demonstrated in vivo and in vitro, and use of an H2A-H2B depleted system demonstrated their central role in LANA’s chromosome binding. Further, we provided a structural description of the interaction of LANA’s N-terminal chromosome association region with the nucleosome using x-ray crystallography. Our data offer further insight into the mechanism of KSHV latency, and also reveal a new concept for a role of the nucleosome as a docking site for other proteins.




PERSPECTIVES

Open Access Article

Protein Tyrosine Phosphatase 1B in Hematopoiesis

Krista M. Heinonen and Michel L. Tremblay
Pages 1053 - 1056
http://dx.doi.org/10.4161/cc.5.10.2735
Abstract | PDF

Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase best known for its role in insulin signaling. Despite the fact that it is highly expressed in hematopoietic tissues and has been shown to downregulate cytokine receptor signaling, no physiological role for PTP-1B in immune regulation had been reported. Our recent results show that the absence of PTP-1B affects murine myelopoiesis through increased phosphorylation of the CSF-1 receptor tyrosine kinase. Here we further discuss the role of PTP-1B in monocyte/macrophage differentiation as well as the implications of our findings in the context of PTP-1B inhibitors.

Open Access Article

Reprogramming of B Lymphoid Cells in Human Lymphoma Pathogenesis

Martin Janz, Bernd Dörken and Stephan Mathas
Pages 1057 - 1061
http://dx.doi.org/10.4161/cc.5.10.2737
Abstract | PDF

Previous hypotheses have stated that differentiated cells lose the ability to change their fate. Using lymphoid development as a model system, recent data have challenged this rigid view of cellular differentiation. It has been shown in mouse models that, under certain conditions, even mature lymphoid cells can display a broad developmental potential, and might even transdifferentiate into other cell types. The relevance of these observations for the physiological ontogenesis of lymhpoid cells or their malignant transformation is currently unclear. Recent data from our laboratory have demonstrated that similar processes can be observed in the malignant Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma (cHL), a common B cell-derived lymphoma. In HRS cells, the B cell-specific homodimer activity of the transcription factor E2A is functionally disrupted by overexpression of the E2A antagonists activated B cell factor 1 (ABF-1) and inhibitor of differentiation 2 (Id2). In consequence, the expression of B cell-specific genes is lost, and B lineage-inappropriate genes are upregulated. These data have demonstrated the plasiticity of human lymphoid cells and offer an explanation for the unique phenotype of cHL. We first summarize data showing the plasticity of lymphoid cells in mouse models, second describe our observations regarding the altered B cell-specific transcription factor network in HRS cells, and third discuss the possible implications of these findings for human lymphoma pathogenesis.

Open Access Article

Double Bolt Regulation of Rad51 by p53: A Role for Transcriptional Repression

Iciar Lazaro-Trueba, Carmen Arias and Augusto Silva
Pages 1062 - 1065
http://dx.doi.org/10.4161/cc.5.10.2764
Abstract | PDF

The regulation of homologous recombination (HR) by p53 has been currently associated with its non-transactivating function; now the transcriptional repression of the Rad51 gene by p53 has been elucidated. This extra control by p53 involves the transcriptional down-regulation of Rad51 protein, which in turn accounts for the reduction of functional Rad51 foci. Down regulation of Rad51 protein might be relevant, considering that Rad51 is a rate-limiting factor in HR. Moreover, impaired Rad51-repression by p53 mutant proteins may contribute to malignant transformation.

Open Access Article

Bur1/Bur2 and the Ctk Complex in Yeast: The Split Personality of Mammalian P-TEFb

Adam Wood and Ali Shilatifard
Pages 1066 - 1068
http://dx.doi.org/10.4161/cc.5.10.2769
Abstract | PDF

Eukaryotic organisms possess a host of factors that regulate transcriptional elongation. In higher eukaryotes, the transcription factor P-TEFbβ not only regulates phosphorylation of the RNA polymerase II C-terminal domain, but it also inhibits the action of transcriptional repressors and is required for the association of several elongation factors with the transcribing polymerase. In the yeast Saccharomyces cerevisiae, the cyclin dependent kinases Bur1/Bur2 and Ctk complex (Ctk1, 2 and 3) are also able to impact several aspects of transcription. Together, these two kinase complexes appear to functionally reconstitute the activity of P-TEFβ in yeast. Recent findings regarding the role of these kinases in histone tail modifications and transcriptional regulation is briefly reviewed below.

Open Access Article

GDF3 at the Crossroads of TGF-beta Signaling

Ariel J. Levine and Ali H. Brivanlou
Pages 1069 - 1073
http://dx.doi.org/10.4161/cc.5.10.2771
Abstract | PDF

Embryonic stem (ES) cells present an excellent system for addressing the relevance of our current knowledge about how cell fate is determined and how cells integrate multiple signals into a single outcome as a function of time. Many of the factors that mediate these phenomena have been discovered through classical embryological experiments and are organized into several major signal transduction pathways including TGF-β/BMP, Jak-STAT, Hedgehog, Wnt, Notch and FGF/MAPK.1 This review will summarize the current understanding of TGF-β signaling in ES and focus on early embryological roles of the TGF-β member, GDF-3. GDF-3 is associated with the undifferentiated state of ES cells and two recent and contradictory reports examined the function and mechanism of GDF-3 in the context of both stem cells and early embryonic differentiations. While Levine and Brivanlou found that GDF-3 inhibits its own subfamily members (the BMPs), Chen and colleagues found that GDF-3 acts as a nodal-like TGF-β ligand. These combined findings raise the intriguing possibility that GDF-3 acts as a bi-functional protein, to regulate the balance between the two modes of TGF-β signaling.




REVIEWS

Open Access Article

Genetically Engineered Human Cancer Models Utilizing Mammalian Transgene Expression

S. DiSean Kendall, Stacey J. Adam and Christopher M. Counter
Pages 1074 - 1079
http://dx.doi.org/10.4161/cc.5.10.2734
Abstract | PDF

Cancer models are vital to cancer biology research, and multiple cancer models are currently available that utilize either murine or human cells, each with particular strengths and weaknesses. The ability to transform primary human cells into tumors through the expression of specific transgenes offers many advantages as a cancer model, including genetic malleability and the ability to transform specific cell types. Until recently, the conversion of primary human cells into tumors through transgene expression required the use of viral genetic elements, which unfortunately adds uncertainty regarding which cancer pathways are affected and how they are affected. In recent years multiple reports have described the transformation of primary human cells into tumors using only mammalian transgenes. This review focuses on these five cancer models, comparing the different cell types which were transformed into tumors and which transgenes were expressed, as well as the cancer pathways affected in the disparate models. These genetically-engineered human cancer models offer a valuable tool to complement existing cancer models and further cancer research.

Open Access Article

Human Polynucleotide Phosphorylase (hPNPase^old-35): An RNA Degradation Enzyme with Pleiotrophic Biological Effects

Devanand Sarkar and Paul B. Fisher
Pages 1080 - 1084
http://dx.doi.org/10.4161/cc.5.10.2741
Abstract | PDF

Identification of small inhibitory RNAs and microRNA established that regulation of RNA metabolism plays an essential role in controlling intracellular biochemical processes. Interferons induce a number of RNA degradation enzymes involved in innate immunity by degrading viral RNAs. We cloned human polynucleotide phosphorylase (hPNPase^old-35), a type I interferon-inducible 3’-5’ exoribonuclease, as a transcript induced during terminal differentiation and senescence, two physiological processes marked by irreversible growth arrest. Our studies in the last four years show that hPNPase^old-35 plays an essential role in mediating IFN-mediated growth inhibition and its upregulation might mediate chronic inflammatory pathological processes during aging. The present review recaps these findings and provides a framework for the future understanding of the versatile functions of this interesting molecule.




BRIEF REPORT

Open Access Article

UV-Mediated NF-κB Activation is Abolished in Deficient XPC/D Primary Fibroblasts

Alysson R. Muotri, Virginie Bottero, Vinay Tergaonkar and Ricardo G. Correa
Pages 1085 - 1089
http://dx.doi.org/10.4161/cc.5.10.2780
Abstract | PDF

Genetic pathologies involving deficits in DNA repair, like xeroderma pigmentosum (XP), show recurrent cell death, tissue degeneration and oncogenesis due to high sensitivity to ultraviolet radiation (UV). Various inducers including UV activate NF-κB, a pathway largely involved in cell proliferation and apoptosis. However, the mechanism(s) involving NF-κB activation by UV are poorly understood. To improve this knowledge, we examined NF-κB in two XP cell groups (XPC and XPD/TTD). XPC/D primary fibroblasts possess functional NF-κB dimers, and pro-inflammatory cytokines consistently activate NF-κB pathway. Contrarily, UV-mediated NF-κB activation is practically absent, whereas κB-specific DNA binding and transcriptional activity are dramatically undermined. These results indicate that lack of UV responsiveness at the NF-κB level is a common feature of XPC/D cells, suggesting that XP proteins might act upstream on NF-κB activity induced by UV. These observations help us to better understand the UV sensitivity and compromised survival of XP deficient cells.




ANALYTICAL REPORT

Open Access Article

Theoretical Proposal: Allele Dosage of MAP2K4/MKK4 Could Rationalize Frequent 17p Loss in Diverse Human Cancers

Steven C. Cunningham, Eike Gallmeier, Tomas Hucl, David A. Dezentje, Kotb Abdelmohsen, Myriam Gorospe and Scott E. Kern
Pages 1090 - 1093
http://dx.doi.org/10.4161/cc.5.10.2805
Abstract | PDF

Although aneuploidy is a global genomic abnormality present in most human cancers, the clonal selection model best explains the action of select activating mutations in oncogenes and homozygous losses of tumor-suppressor genes. Simple gene dosage changes are difficult however, to incorporate into this model, in part due to negative feedback loops that govern major cancer mutational targets (eg, TP53, PTCH, SMAD4) and essentially preclude a haploinsufficient phenotype. The 17p conundrum may offer a clue to reconciling this difficulty: In comparison to the moderate mutation rate of TP53, many tumors have a disproportionately high frequency of loss of 17p. This discrepancy, and similarly discrepancies at other sites of LOH, has long been thought to be due to the presence of undiscovered yet frequently mutated tumor-suppressor genes. However, over 15 years of searching for this grail has distributed bountiful disappointment. It is perhaps time to seriously consider an alternative explanation. Located on 17p adjacent to the TP53 gene, MKK4 is one of the most consistently mutated genes across tumor types, and is located on one of the most frequently lost arms in the human genome. We theorized that a gene dosagedependent phenotype of MKK4 could plausibly promote the emergence of 17p LOH and thereby the probability of evolving the biallelic inactivation of TP53. Using MKK4 somatic human knockout cancer cells, we observed the proof-of-principle in the downstream gene dosage-dependent phenotypes: heterozygous and homozygous knockouts were progressively deficient in Mkk4 protein, in stress-induced phosphorylation of Jnk, and the resultant upregulation of JUN mRNA. These observations highlight a lack of compensatory regulation when gene dosage changes perturb the Jnk-Jun relationship. Consideration of gene dosage changes specifically affecting members of positive feedback loops may permit integration of the aneuploidy process into a conventional model of clonal selection in tumorigenesis.




REPORTS

Open Access Article

Human Shugoshin Mediates Kinetochore-Driven Formation of Kinetochore Microtubules

Hideaki Suzuki, Nobutake Akiyama, Megumi Tsuji, Toya Ohashi, Saburo Saito and Yoshikatsu Eto
Pages 1094 - 1101
http://dx.doi.org/10.4161/cc.5.10.2747
Abstract | PDF

The conserved protein Shugoshin (Sgo) plays a role in the maintenance of centromeric cohesion in mitosis and meiosis. Human Shugoshin (hSgo) was first identified as an overexpressed protein in breast cancers. Here we demonstrate that hSgo mediates kinetochore-driven formation of kinetochore microtubules (MTs) during bipolar spindle assembly. The regulated overexpression of full-length hSgo, or of truncated proteins containing both the conserved N-terminal coiled-coil domain and C-terminal basic domain, resulted in hSgo localization at centromere at early mitosis and was associated with aberrant nucleation and formation of bundles of kinetochore MTs. The mid-portion of hSgo, between the N- and C-terminal domains, includes both a functional domain for centromeric cohesion and a regulatory domain for spindle assembly. The cells overexpressing natural alternative splicing isoforms, which are almost completely defective for the mid-portion of the hSgo protein, showed premature centromere separation (PCS) and aberrant MT connections. These isoforms are mildly overexpressed in HEK293 cells. On the other hand, cells expressing a truncated protein, defective in the lysine-rich region of the mid-portion, arrested at mitosis due to persistent abnormal MT connections and not because of PCS. Aberrant MT connections were predominantly observed in spindle regions where chromosomes were clustered. Interestingly, we also found that hSgo is rapidly exchanged at kinetochores at early mitosis. Based on these results, we conclude that hSgo may be diffusible and have a role in proper kinetochores-MTs attachment.

Open Access Article

Repression of New p53 Targets Revealed by ChIP on Chip Experiments

Michele Ceribelli, Myriam Alcalay, Maria Alessandra Viganò and Roberto Mantovani
Pages 1102 - 1110
http://dx.doi.org/10.4161/cc.5.10.2777
Abstract | PDF

Following DNA-damage, the tumor suppressor p53 activates G1/S blocking and apoptotic genes, and represses other genes, including those involved in G2/M transition. In this latter system, it acts through the CCAAT-binding histone-like NF-Y. Several groups have reported that p53 is associated to promoters in unstressed conditions. We developed an oligo-based array containing 179 human promoters, enriched in genes involved in the DNA-damage and ER-stress response. We performed ChIP on chip experiments with p53 and NF-Y in cells under normal growing conditions. We identified 46 new p53 targets and noted (i) a significant enrichment in genes of the ER-stress response, including crucial regulators such as XBP1 and C/EBPβ; (ii) genes whose products are involved in the regulation of p53 function. Several genes were validated by conventional ChIP. DNA-damage dependent PCAF-mediated acetylation was observed on most, but not all promoters. The effect of p53 activation was checked by RT-PCR and transfections in HCT116 wt, E6 and p53-/- cells: most promoters were actively repressed upon Adriamycin treatment or following p53 transfection in p53-/- cells. In particular, the behaviour of some of the genes (BRAC1, RAD23 and RAD17) is consistent with a feed-back loop regulation on p53 levels. Finally, there is a large overlap (66%) between p53 and NF-Y targets. Our data reinstate the physiological importance of p53 promoter recognition and direct transcriptional repression as a mechanism to cope with DNA-damage.

Open Access Article

The TRIP-Br Family of Transcriptional Regulators is Essential for the Execution of Cyclin E-Mediated Cell Cycle Progression

Khe Guan Sim, Jit Kong Cheong and Stephen I-Hong Hsu
Pages 1111 - 1115
http://dx.doi.org/10.4161/cc.5.10.2797
Abstract | PDF

The G1 D-type cyclins, in conjunction with cyclin-dependent kinases Cdk4 and Cdk6, play key roles in the execution of mitogen-induced cellular proliferation. TRIPBr1, a member of the TRIP-Br family of transcriptional regulators, has been implicated in the regulation of Cdk4/cyclin D activity. To further elucidate the functional role(s) of the TRIP-Br proteins in mitogenic signaling, we have developed the synthetic DNA enzymes E-Br1 and E-Br2 to specifically knock down the serum-inducible expression of TRIP-Br1 and TRIP-Br2, respectively, in WI-38 human fibroblasts in culture, as well as generated TRIP-Br2 null primary embryonic fibroblasts from a novel TRIP-Br2 knockout mouse model. Both strategies consistently reveal that ablation of TRIP-Br1 or TRIP-Br2 expression disrupts mitogenic signaling in a manner that suppresses serum-induced cyclin E expression, S phase entry and cellular proliferation. We conclude that both TRIP-Br1 and TRIP-Br2 are required for proper transduction of mitogenic signals and execution of serum-inducible cell cycle progression.

Open Access Article

The Loss of γH2AX Signal is a Marker of DNA Double Strand Breaks Repair Only at Low Levels of DNA Damage

Fanny Bouquet, Catherine Muller and Bernard Salles
Pages 1116 - 1122
http://dx.doi.org/10.4161/cc.5.10.2799
Abstract | PDF

The induction of DNA double-strand breaks (DSBs) by genotoxic treatment leads to high toxicity and genetic instability. Various approaches have been undertaken to quantify the number of breaks and to follow the kinetic of DSB repair. Recently, the phosphorylation of the variant histone H2AX (named γH2AX), quantified by specific immunodetection approaches, has provided a valuable and highly sensitive method to monitor DSBs formation. Although it is admitted that the number of γH2AX foci reflected that of DSBs, contradictory reports leave open the question of a link between the disappearance of γH2AX signal and DSBs repair. We determined γH2AX expression (i) in cells either proficient or not in DSBs repair capacity, (ii) after exposure to ionizing radiation (IR) or calicheamicin γ1, a radiomimetic compound, (iii) and by three different immunodetection methods, foci numbering, flow cytometry or Western blotting. We showed here that γH2AX loss correlates with DSB repair activity only at low cytotoxic doses, when less than 100-150 DSBs breaks per genome are produced, independently of the method used. In addition, in DNA repair proficient cells, the early decrease in the number and intensity of γH2AX foci observed after a 2 Gy exposure was not associated with a significant change in the global γH2AX level as determined by Western blotting or flow cytometry. These results suggest that the dephosphorylation step of γH2AX may be limiting and that the loss of foci is mediated not only by γH2AX dephosphorylation but also through its redistribution towards the chromatin.




VIEWS AND COMMENTARIES

Open Access Article

CDK2-Activating Kinase (CAK): More Questions than Answers

Tarek Abbas and Anindya Dutta
Pages 1123 - 1124
http://dx.doi.org/10.4161/cc.5.10.2819
Abstract | PDF

Commentary to:

The cyclin-dependent kinase (CDK) Family member PNQALRE/CCRK supports cell proliferation but has no intrinsic CDK-activating kinase (CAK) activity.
Lara Wohlbold, Stéphane Larochelle, Jack C.-F. Liao, Geulah Livshits, Juliet Singer, Kevan M. Shokat and Robert P. Fisher
Cell Cycle. 2006 Mar;5(5):546-54.