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1.  Peroxisomes take shape 
Peroxisomes carry out various oxidative reactions that are tightly regulated to adapt to the changing needs of the cell and varying external environments. Accordingly, they are remarkably fluid and can change dramatically in abundance, size, shape and content in response to numerous cues. These dynamics are controlled by multiple aspects of peroxisome biogenesis that are coordinately regulated with each other and with other cellular processes. Ongoing studies are deciphering the diverse molecular mechanisms that underlie biogenesis and how they cooperate to dynamically control peroxisome utility. These important challenges should lead to an understanding of peroxisome dynamics that can be capitalized upon for bioengineering and the development of therapies to improve human health.
doi:10.1038/nrm3700
PMCID: PMC4060825  PMID: 24263361
2.  Dynamic niches in the origination and differentiation of haematopoietic stem cells 
Haematopoietic stem cells (HSCs) are multipotent, self-renewing progenitors that generate all mature blood cells. HSC function is tightly controlled to maintain haematopoietic homeostasis, and this regulation relies on specialized cells and factors that constitute the haematopoietic ‘niche’, or microenvironment. Recent discoveries, aided in part by technological advances in in vivo imaging, have engendered a new appreciation for the dynamic nature of the niche, identifying novel cellular and acellular niche components and uncovering fluctuations in the relative importance of these components over time. These new insights significantly improve our understanding of haematopoiesis and raise fundamental questions about what truly constitutes a stem cell niche.
doi:10.1038/nrm3184
PMCID: PMC4040463  PMID: 21886187
3.  TETonic shift: biological roles of TET proteins in DNA demethylation and transcription 
In many organisms, the methylation of cytosine in DNA has a key role in silencing ‘parasitic’ DNA elements, regulating transcription and establishing cellular identity. The recent discovery that ten-eleven translocation (TET) proteins are 5-methylcytosine oxidases has provided several chemically plausible pathways for the reversal of DNA methylation, thus triggering a paradigm shift in our understanding of how changes in DNA methylation are coupled to cell differentiation, embryonic development and cancer.
doi:10.1038/nrm3589
PMCID: PMC3804139  PMID: 23698584
4.  Origins and implications of pluripotent stem cell variability and heterogeneity 
Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in their capacity to differentiate into desired cell types in vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could ‘lock’ the pluripotency network resulting in residual pluripotent cells or alter the signalling response of developmental pathways leading to lineage bias. The molecular contributors to functional variability and heterogeneity in both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are only beginning to emerge, yet they are crucial to the future of the stem cell field.
doi:10.1038/nrm3584
PMCID: PMC3980962  PMID: 23673969
5.  Specialized ribosomes: a new frontier in gene regulation and organismal biology 
Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than intrinsic regulatory capacity in mRNA translation. However, emerging studies reveal that ribosome activity may be highly regulated. Heterogeneity in ribosome composition resulting from differential expression and post-translational modifications of ribosomal proteins, ribosomal RNA (rRNA) diversity and the activity of ribosome-associated factors may generate ‘specialized ribosomes’ that have a substantial impact on how the genomic template is translated into functional proteins. Moreover, constitutive components of the ribosome may also exert more specialized activities by virtue of their interactions with specific mRNA regulatory elements such as internal ribosome entry sites (IRESs) or upstream open reading frames (uORFs). Here we discuss the hypothesis that intrinsic regulation by the ribosome acts to selectively translate subsets of mRNAs harbouring unique cis-regulatory elements, thereby introducing an additional level of regulation in gene expression and the life of an organism.
doi:10.1038/nrm3359
PMCID: PMC4039366  PMID: 22617470
6.  Synthetic biology in mammalian cells: Next generation research tools and therapeutics 
Recent progress in DNA manipulation and gene circuit engineering has greatly improved our ability to programme and probe mammalian cell behaviour. These advances have led to a new generation of synthetic biology research tools and potential therapeutic applications. Programmable DNA-binding domains and RNA regulators are leading to unprecedented control of gene expression and elucidation of gene function. Rebuilding complex biological circuits such as T cell receptor signalling in isolation from their natural context has deepened our understanding of network motifs and signalling pathways. Synthetic biology is also leading to innovative therapeutic interventions based on cell-based therapies, protein drugs, vaccines and gene therapies.
doi:10.1038/nrm3738
PMCID: PMC4032074  PMID: 24434884
7.  TGFβ signalling in context 
The basic elements of the transforming growth factor-β (TGFβ) pathway were revealed more than a decade ago. Since then, the concept of how the TGFβ signal travels from the membrane to the nucleus has been enriched with additional findings, and its multifunctional nature and medical relevance have relentlessly come to light. However, an old mystery has endured: how does the context determine the cellular response to TGFβ? Solving this question is key to understanding TGFβ biology and its many malfunctions. Recent progress is pointing at answers.
doi:10.1038/nrm3434
PMCID: PMC4027049  PMID: 22992590
8.  MicroRNAs in Metabolism and Metabolic Disorders 
MicroRNAs (miRNAs) have recently emerged as key regulators of metabolism. For example, miR-33a and b play a crucial role in controlling cholesterol and lipid metabolism in concert with their host genes, the SREBP transcription factors. Metabolic miRNAs such as miR-103 and miR-107 regulate insulin and glucose homeostasis, while others, such as miR-34a, may be key regulators of hepatic lipid homeostasis. The discovery of circulating miRNAs has highlighted their potential as both endocrine signalling molecules and disease markers. Dysregulation of miRNAs may contribute to metabolic abnormalities, suggesting that miRNAs may potentially serve as therapeutic targets to ameliorate cardiometabolic disorders.
doi:10.1038/nrm3313
PMCID: PMC4021399  PMID: 22436747
9.  Re-starting life: Fertilization and the transition from meiosis to mitosis 
Fertilization triggers a complex cellular programme that transforms two highly specialized meiotic germ cells, the oocyte and the sperm, into a totipotent mitotic embryo: linkages between sister chromatids are remodelled to support the switch from reductional meiotic to equational mitotic divisions; the centrosome, which is absent from the egg, needs to be reintroduced; the axis of cell division is shifted from extremely asymmetric to symmetric; genomic imprinting is selectively erased and re-established; and protein expression shifts from translational control back to transcriptional control. Recent work has started to reveal how this remarkable transition from meiosis to mitosis is achieved.
doi:10.1038/nrm3643
PMCID: PMC4021448  PMID: 23942453
10.  Functions and mechanics of dynein motor proteins 
Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and intracellular transport. The large mass and complexity of dynein motors have made elucidating their mechanisms a sizable task. Yet, through a combination of approaches, including X-ray crystallography, cryo-electron microscopy, single-molecule assays and biochemical experiments, important progress has been made towards understanding how these giant motor proteins work. From these studies, a model for the mechanochemical cycle of dynein is emerging, in which nucleotide-driven flexing motions within the AAA+ ring of dynein alter the affinity of its microtubule-binding stalk and reshape its mechanical element to generate movement.
doi:10.1038/nrm3667
PMCID: PMC3972880  PMID: 24064538
11.  Amino acid signalling upstream of mTOR 
Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H+-ATPase (v-ATPase).
doi:10.1038/nrm3522
PMCID: PMC3988467  PMID: 23361334
12.  Assembly of allosteric macromolecular switches: lessons from PKA 
Protein kinases are dynamic molecular switches that have evolved to be only transiently activated. Kinase activity is embedded within a conserved kinase core, which is typically regulated by associated domains, linkers and interacting proteins. Moreover, protein kinases are often tethered to large macromolecular complexes to provide tighter spatiotemporal control. Thus, structural characterization of kinase domains alone is insufficient to explain protein kinase function and regulation in vivo. Recent progress in structural characterization of cyclic AMP-dependent protein kinase (PKA) exemplifies how our knowledge of kinase signalling has evolved by shifting the focus of structural studies from single kinase subunits to macromolecular complexes.
doi:10.1038/nrm3432
PMCID: PMC3985763  PMID: 22992589
13.  Self-consumption: the interplay of autophagy and apoptosis 
Autophagy and apoptosis control the turnover of organelles and proteins within cells, and of cells within organisms, respectively, and many stress pathways sequentially elicit autophagy, and apoptosis within the same cell. Generally autophagy blocks the induction of apoptosis, and apoptosis-associated caspase activation shuts off the autophagic process. However, in special cases, autophagy or autophagy-relevant proteins may help to induce apoptosis or necrosis, and autophagy has been shown to degrade the cytoplasm excessively, leading to ‘autophagic cell death’. The dialogue between autophagy and cell death pathways influences the normal clearance of dying cells, as well as immune recognition of dead cell antigens. Therefore, the disruption of the relationship between autophagy and apoptosis has important pathophysiological consequences.
doi:10.1038/nrm3735
PMCID: PMC3970201  PMID: 24401948
14.  NMD: a multifaceted response to premature translational termination 
Although most mRNA molecules derived from protein-coding genes are destined to be translated into functional polypeptides, some are eliminated by cellular quality control pathways that collectively perform the task of mRNA surveillance. In the nonsense-mediated mRNA decay (NMD) pathway premature translation termination promotes the recruitment of a set of factors that destabilize a targeted mRNA. The same factors also appear to play key roles in repressing the translation of the mRNA, dissociating its terminating ribosome and mRNP proteins, promoting the degradation of its truncated polypeptide product, and possibly even feeding back to the site of transcription to interfere with splicing of the primary transcript.
doi:10.1038/nrm3454
PMCID: PMC3970730  PMID: 23072888
15.  Understanding the language of Lys36 methylation at histone H3 
Histone side chains are post-translationally modified at multiple sites, including at Lys36 on histone H3 (H3K36). Several enzymes from yeast and humans, including the methyltransferases SET domain-containing 2 (Set2) and nuclear receptor SET domain- containing 1 (NSD1), respectively, alter the methylation status of H3K36, and significant progress has been made in understanding how they affect chromatin structure and function. Although H3K36 methylation is most commonly associated with the transcription of active euchromatin, it has also been implicated in diverse processes, including alternative splicing, dosage compensation and transcriptional repression, as well as DNA repair and recombination. Disrupted placement of methylated H3K36 within the chromatin landscape can lead to a range of human diseases, underscoring the importance of this modification.
doi:10.1038/nrm3274
PMCID: PMC3969746  PMID: 22266761
16.  Asymmetric cell division: recent developments and their implications for tumour biology 
The ability of cells to divide asymmetrically is essential for generating diverse cell types during development. The past 10 years have seen tremendous progress in our understanding of this important biological process. We have learned that localized phosphorylation events are responsible for the asymmetric segregation of cell fate determinants in mitosis, and that centrosomes and microtubules play important roles. The relevance of asymmetric cell division for stem cell biology has added a new dimension, and exciting connections between asymmetric cell division and tumorigenesis have begun to emerge.
doi:10.1038/nrm3010
PMCID: PMC3941022  PMID: 21102610
17.  Vertebrate protein glycosylation: diversity, synthesis and function 
Protein glycosylation is a ubiquitous post-translational modification found in all domains of life. Despite their significant complexity in animal systems, glycan structures have crucial biological and physiological roles, from contributions in protein folding and quality control to involvement in a large number of biological recognition events. As a result, they impart an additional level of ‘information content’ to underlying polypeptide structures. Improvements in analytical methodologies for dissecting glycan structural diversity, along with recent developments in biochemical and genetic approaches for studying glycan biosynthesis and catabolism, have provided a greater understanding of the biological contributions of these complex structures in vertebrates.
doi:10.1038/nrm3383
PMCID: PMC3934011  PMID: 22722607
18.  The final steps of integrin activation: the end game 
Cell-directed changes in the ligand-binding affinity (‘activation’) of integrins regulate cell adhesion and migration, extracellular matrix assembly and mechanotransduction, thereby contributing to embryonic development and diseases such as atherothrombosis and cancer. Integrin activation comprises triggering events, intermediate signalling events and, finally, the interaction of integrins with cytoplasmic regulators, which changes an integrin’s affinity for its ligands. The first two events involve diverse interacting signalling pathways, whereas the final steps are immediately proximal to integrins, thus enabling integrin-focused therapeutic strategies. Recent progress provides insight into the structure of integrin transmembrane domains, and reveals how the final steps of integrin activation are mediated by integrin-binding proteins such as talins and kindlins.
doi:10.1038/nrm2871
PMCID: PMC3929966  PMID: 20308986
19.  Ras oncogenes: split personalities 
Extensive research on the Ras proteins and their functions in cell physiology over the past 30 years has led to numerous insights that have revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. Despite great strides in our understanding of the molecular and cellular mechanisms of action of the Ras proteins, the expanding roster of their downstream effectors and the complexity of the signalling cascades that they regulate indicate that much remains to be learnt.
doi:10.1038/nrm2438
PMCID: PMC3915522  PMID: 18568040
20.  The many sides of CIN 
doi:10.1038/nrm3666
PMCID: PMC3914543  PMID: 24061225
21.  The MRE11 complex: starting from the ends 
The maintenance of genome stability depends on the DNA damage response (DDR), which is a functional network comprising signal transduction, cell cycle regulation and DNA repair. The metabolism of DNA double-strand breaks governed by the DDR is important for preventing genomic alterations and sporadic cancers, and hereditary defects in this response cause debilitating human pathologies, including developmental defects and cancer. The MRE11 complex, composed of the meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin) proteins is central to the DDR, and recent insights into its structure and function have been gained from in vitro structural analysis and studies of animal models in which the DDR response is deficient.
doi:10.1038/nrm3047
PMCID: PMC3905242  PMID: 21252998
22.  Charity begins at home: non-coding RNA contributes to DNA repair 
During the past decade, evolutionarily conserved non-coding (nc) RNAs, specifically microRNAs (miRNA), have been characterized as regulators of almost every cellular process and signalling pathway. There is now emerging evidence that this new class of regulators also impinges on the DNA damage response (DDR). Both miRNAs and other small ncRNAs are induced at DNA breaks and mediate the repair process. These intriguing observations raise the possibility that crosstalk between ncRNAs and the DDR might provide a means of efficient and accurate DNA repair and facilitate the maintenance of genomic stability.
doi:10.1038/nrm3523
PMCID: PMC3904369  PMID: 23385724
23.  BRCA1 and its toolbox for the maintenance of genome integrity 
The breast and ovarian cancer type 1 susceptibility protein (BRCA1) has pivotal roles in the maintenance of genome stability. Studies support that BRCA1 exerts its tumour suppression function primarily through its involvement in cell cycle checkpoint control and DNA damage repair. In addition, recent proteomic and genetic studies have revealed the presence of distinct BRCA1 complexes in vivo, each of which governs a specific cellular response to DNA damage. Thus, BRCA1 is emerging as the master regulator of the genome through its ability to execute and coordinate various aspects of the DNA damage response.
doi:10.1038/nrm2831
PMCID: PMC3899800  PMID: 20029420
24.  Open chromatin in pluripotency and reprogramming 
Pluripotent stem cells can be derived from embryos or induced from adult cells by reprogramming. They are unique from any other stem cell in that they can give rise to all cell types of the body. Recent findings indicate that a particularly open chromatin state contributes to maintenance of pluripotency. Two emerging principles are that: specific factors maintain a globally open chromatin state that is accessible for transcriptional activation; and other chromatin regulators contribute locally to the silencing of lineage-specific genes until differentiation is triggered. These same principles may apply during reacquisition of an open chromatin state upon reprogramming to pluripotency, and during de-differentiation in cancer.
doi:10.1038/nrm3036
PMCID: PMC3891572  PMID: 21179060
25.  Transcription-independent functions of MYC: regulation of translation and DNA replication 
Nature reviews. Molecular cell biology  2008;9(10):10.1038/nrm2467.
MYC is a potent oncogene that drives unrestrained cell growth and proliferation. Shortly after its discovery as an oncogene, the MYC protein was recognized as a sequence-specific transcription factor. Since that time, MYC oncogene research has focused on the mechanism of MYC-induced transcription and on the identification of MYC transcriptional target genes. Recently, MYC was shown to control protein expression through mRNA translation and to directly regulate DNA replication, thus initiating exciting new areas of oncogene research.
doi:10.1038/nrm2467
PMCID: PMC3880805  PMID: 18698328

Results 1-25 (147)