A novel role for Greatwall kinase in recovery from DNA damage

Activation of the DNA damage response (DDR) is critical for genomic integrity and tumor suppression. The occurrence of DNA damage quickly evokes the DDR through ATM/ATR-dependent signal transduction, which promotes DNA repair and activates the checkpoint to halt cell cycle progression (Halazonetis et al., 2008; Motoyama and Naka, 2004; Zhou and Elledge, 2000). The "turn off" process of the DDR upon satisfaction of DNA repair, also known as "checkpoint recovery", involves deactivation of DDR elements, but the mechanism is poorly understood. Greatwall kinase (Gwl) has been identified as a key element in the G2/M transition (Archambault et al., 2007; Jackson, 2006; Zhao et al., 2008; Yu et al., 2004; Yu et al., 2006; Zhao et al., 2006) and helps maintain M phase through inhibition of PP2A/B55δ (Burgess et al., 2010; Castilho et al., 2009; Goldberg, 2010; Lorca et al., 2010; Vigneron et al., 2009), the principal phosphatase for Cdk-phosphorylated substrates. Here we show that Gwl also promotes recovery from DNA damage and is itself directly inhibited by the DNA damage response (DDR). In Xenopus egg extracts, immunodepletion of Gwl increased the DDR to damaged DNA, whereas addition of wild type, but not kinase dead Gwl, inhibited the DDR. The removal of damaged DNA from egg extracts leads to recovery from checkpoint arrest and entry into mitosis, a process impaired by Gwl depletion and enhanced by Gwl over-expression. Moreover, activation of Cdk1 after the removal of damaged DNA is regulated by Gwl. Collectively, these results defines Gwl as a new regulator of the DDR, which plays an important role in recovery from DNA     

Unexpected pieces to the senescence puzzle

Although initially described as the end state of cells after extended rounds of division in culture, it is now clear that cellular senescence induced by different stimuli plays an important role in tumor suppression in vivo. Three recent studies in Cell report that secreted proteins play an important role in enforcing the senescence response (Acosta et al., 2008; Kuilman et al., 2008; Wajapeyee et al., 2008). These new studies identify unanticipated contributors to this tumor-suppressing cell state.     

Swapping nucleotides, tuning Hsp70

Molecular chaperones such as heat shock protein 70 (Hsp70) are crucial for protein folding. Crystal structures of Hsp70 in a complex with the nucleotide exchange factor (NEF) Hsp110 reported in this issue of Cell (Polier et al., 2008) and in Molecular Cell (Schuermann et al., 2008) provide new insights into how NEF action specifies Hsp70 cellular function.     

Insect odorant receptors: channeling scent

Odorant detection in insects involves heterodimers between an odorant receptor (OR) and a conserved seven-transmembrane protein called Or83b, but the exact mechanism of OR signal transduction is unclear. Two recent studies in Nature (Sato et al., 2008; Wicher et al., 2008) now reveal that these OR-Or83b heterodimers form odorant-gated ion channels, revealing a surprising new mode of olfactory transduction.     

Substrate selectivity APPLies to Akt

The protein kinase Akt occupies a central position in multiple signaling pathways. Although numerous Akt substrates have been identified, less is known about the factors that regulate specific cellular responses to Akt signaling. In this issue, Schenck et al. (2008) demonstrate that the endosomal protein Appl1 modulates Akt's substrate selectivity to promote cell survival during zebrafish development.     

浙江天台盆地晚白垩世恐龙蛋新类型(英文)

浙江天台盆地上白垩统赖家组和赤城山组是我国最重要的恐龙蛋化石产出地层之一。近年来,我们对天台盆地陆相红层中的恐龙蛋化石层位进行了详细厘定,对恐龙蛋类型进行了系统描述,并对前人报道的一些属种进行了分类订正。研究显示,天台恐龙蛋化石群基本上可分为7蛋科、12蛋属和15蛋种,代表了我国晚白垩世早期的恐龙蛋化石组合。本文简要报道了主要产自天台盆地赤城山组的双塘似蜂窝蛋(新蛋属、新修订种)、木鱼山半蜂窝蛋(新蛋属、新蛋种)、国清寺副蜂窝蛋(新修订种)、天台棱柱形蛋(新修订种)和张头槽马赛克蛋(新蛋属、新修订种)等3新蛋属、5新蛋种和修订种的主要鉴定特征,并建立一新蛋科——似蜂窝蛋科。     

Highways for mRNA transport

Two new studies reveal the role of microtubule polarity in the asymmetric localization of mRNAs. In this issue of Cell, Zimyanin et al. (2008) show that the asymmetric localization of oskar mRNA in fruit fly oocytes results from a slight bias in the direction of its transport. Meanwhile, Messitt et al. (2008) reporting in Developmental Cell find a subpopulation of microtubules that is critical for the asymmetric distribution of Vg1 mRNA in frog oocytes.     

ATP-dependent chromatin remodeling complex SWI/SNF in cardiogenesis and cardiac progenitor cell development

The recent identification of cardiac progenitor cells (CPCs) provides a new paradigm for studying and treating heart disease.To realize the full potential of CPCs for therapeutic purposes,it is essenti...     

A SNO storm in skeletal muscle

Dysregulated S-nitrosylation of proteins characterizes a broad array of human disorders, but its role in disease etiology is not well understood. Two new studies (Durham et al., 2008; Bellinger et al., 2008) now show that hyper-S-nitrosylation of the ryanodine receptor calcium release channel (RyR1) in skeletal muscle disrupts calcium ion flux. This disruption underlies the impaired contractility and cellular damage of skeletal muscle during strenuous exercise and in a spectrum of congenital muscle disorders including malignant hyperthermia.     

A tale of too many centrosomes

Having the correct number of centrosomes is crucial for proper chromosome segregation during cell division and for the prevention of aneuploidy, a hallmark of many cancer cells. Several recent studies (Basto et al., 2008; Kwon et al., 2008; Yang et al., 2008) reveal the importance of mechanisms that protect against the consequences of harboring too many centrosomes.     

The Yin and Yang of treating BRCA-deficient tumors

The myriad changes that occur during the malignant progression of cancer cells present challenges to both clinicians and basic scientists. Two new studies in Nature underscore the central role of genome instability in tumor biology (Edwards et al., 2008; Sakai et al., 2008). These reports describe secondary changes in the BRCA2 locus that restore the wild-type reading frame and contribute to the development of resistance to chemotherapeutic agents.     

Transcriptional ShortCUTs

Recent work from Kuehner and Brow (2008) and Thiebaut et al. (2008) in Molecular Cell and Jenks et al. (2008) in Molecular and Cellular Biology reveals that regulated expression of central nucleotide synthesis pathway components directs start site-dependent RNA polymerase II termination.     

Mitochondrial dynamics and apoptosis: a painful separation

Reporting in Molecular Cell, Sheridan et al. (2008) and Breckenridge et al. (2008) show that mitochondrial fragmentation is not required to induce cell death. Meanwhile, Yamaguchi et al. show that proapoptotic Bcl-2 family members promote cytochrome c mobilization through Opa1-mediated cristae remodeling. Therefore, the connection between mitochondrial structure and apoptosis is more complex than previously imagined.     

Re-evaluation on the diversity of the polyphyletic genus Metaurostylopsis (Ciliophora, Hypotricha): ontogenetic, morphologic, and molecular data suggest the establishment of a new genus Apourostylopsis n. g

The urostylid genus Metaurostylopsis Song et al., 2001 was considered to be a well-outlined taxon. Nevertheless, recent evidence, including morphological, ontogenetic, and molecular information, have consistently revealed conflicts among congeners, regarding their systematic relationships, ciliature patterns, and origins of ciliary organelles. In the present work, the morphogenetic and morphogenetic features were re-checked and compared, and the phylogeny of nominal species was analysed based on information inferred from the small subunit ribosomal RNA (SS rRNA) gene sequence. In addition, the binary divisional process in a new isolate of Metaurostylopsis struederkypkeae Shao et al., 2008 is described. All results obtained reveal that the genus is a polyphyletic assemblage whose nominal congeners fall into three clades within the core Urostylida, based on SS rRNA gene sequences. These three clades not match the groups inferred from morphological/morphogenetical evidences. Some conflicting data from molecular and ontogenetic studies also indicate that single-gene information might not be consistently reliable in detecting the phylogenetic relationships among closely related groups and comprehensive multi-gene analyses are necessary to give a more exact evaluation for this divergent assemblage. According to our new understandings, five forms are confirmed to be true Metaurostylopsis. The morphotype Metaurostylopsis sinica Shao et al., 2008 should be excluded from the genus and represents a distinct type, and, thus, a new genus Apourostylopsis n. g. with it as the type specie, i.e. Apourostylopsis sinica (Shao et al., 2008) n. comb.     

DeTEKting ubiquitination of APC/C substrates

Regulated protein degradation by the ubiquitin-proteasome pathway ensures the unidirectionality of mitotic progression by removing cell-cycle regulators required at earlier stages. The APC/C ubiquitin-protein ligase targets proteins by appending polyubiquitin degradation signals that are subsequently recognized by the 26S proteasome. Reporting in this issue, Jin et al. (2008) identify a TEK motif in both ubiquitin and substrates of APC/C that mediates assembly of these degradation signals.     

RAD in the realm of next-generation sequencing technologies

The first North American RAD Sequencing and Genomics Symposium, sponsored by Floragenex (http://www.floragenex.com/radmeeting/), took place in Portland, Oregon (USA) on 19 April 2011. This symposium was convened to promote and discuss the use of restriction-site-associated DNA (RAD) sequencing technologies. RAD sequencing is one of several strategies recently developed to increase the power of data generated via short-read sequencing technologies by reducing their complexity (Baird et al. 2008; Huang et al. 2009; Andolfatto et al. 2011; Elshire et al. 2011). RAD sequencing, as a form of genotyping by sequencing, has been effectively applied in genetic mapping and quantitative trait loci (QTL) analyses in a range of organisms including nonmodel, genetically highly heterogeneous organisms (Table 1; Baird et al. 2008; Baxter et al. 2011; Chutimanitsakun et al. 2011; Pfender et al. 2011). RAD sequencing has recently found applications in phylogeography (Emerson et al. 2010) and population genomics (Hohenlohe et al. 2010). Considering the diversity of talks presented during this meeting, more developments are to be expected in the very near future.     

Quantification of random mutations in the mitochondrial genome

Mitochondrial DNA (mtDNA) mutations contribute to the pathology of a number of age-related disorders, including Parkinson disease [A. Bender et al., Nat. Genet. 38 (2006) 515,Y. Kraytsberg et al., Nat. Genet. 38 (2006) 518], muscle-wasting [J. Wanagat, Z. Cao, P. Pathare, J.M. Aiken, FASEB J. 15 (2001) 322], and the metastatic potential of cancers [K. Ishikawa et al., Science 320 (2008) 661]. The impact of mitochondrial DNA mutations on a wide variety of human diseases has made it increasingly important to understand the mechanisms that drive mitochondrial mutagenesis. In order to provide new insight into the etiology and natural history of mtDNA mutations, we have developed an assay that can detect mitochondrial mutations in a variety of tissues and experimental settings [M. Vermulst et al., Nat. Genet. 40 (2008) 4, M. Vermulst et al., Nat. Genet. 39 (2007) 540]. This methodology, termed the Random Mutation Capture assay, relies on single-molecule amplification to detect rare mutations among millions of wild-type bases [J.H. Bielas, L.A. Loeb, Nat. Methods 2 (2005) 285], and can be used to analyze mitochondrial mutagenesis to a single base pair level in mammals.     

Stem cell regulation and host defense: the logic and the paradox

Stem cell-based cardiac regeneration requires a detailed understanding of the factors that induce cardiac lineage commitment. In this issue of Cell Stem Cell, Lindsley et al. (2008) and Bondue et al. (2008) use embryonic stem cells to identify a key role for Mesp1 in this process.