Review Articles

  • Review Article |

    The transcriptional response to hypoxia and the role of hypoxia inducible factors have been extensively studied. Yet, hypoxic cells also adapt to hypoxia by modulating protein synthesis, metabolism and nutrient uptake. Understanding these processes could shed light on pathologies associated with hypoxia, including cardiovascular diseases and cancer, and disease mechanisms, such as inflammation and wound repair.

    • Pearl Lee
    • , Navdeep S. Chandel
    •  & M. Celeste Simon
  • Review Article |

    The mechanical and dynamic properties of microtubules are determined by their complement of subunits, known as tubulin isotypes, and the post-translational modifications found on these isotypes. This concept is known as the ‘tubulin code’. The regulation of microtubules and microtubule-associated proteins by this code is critical for the correct function of a range of tissues. Consequently, recent studies have linked perturbation of the tubulin code to disease, including neurodegenerative diseases.

    • Carsten Janke
    •  & Maria M. Magiera
  • Review Article |

    BRCA1 and its partner BARD1 support repair of double-strand breaks by homologous recombination and protect replication forks from damage. Recent studies have improved our understanding of the molecular mechanisms of these tumour-suppressive functions of BRCA1–BARD1 and how they are subverted in therapy-resistant cancers.

    • Madalena Tarsounas
    •  & Patrick Sung
  • Review Article |

    The MYC oncoproteins are transcription factors, but the molecular mechanism of their oncogenic activity is unclear. MYC proteins promote transcription termination in stress conditions, which is proposed to increase cellular resilience to stress and to promote tumorigenesis independently of changes in the expression of their target genes.

    • Apoorva Baluapuri
    • , Elmar Wolf
    •  & Martin Eilers
  • Review Article |

    Mitochondrial networks are dynamically remodelled via fusion, fission and ultrastructural changes to mitochondrial membranes. These mitochondrial membrane dynamics are tightly coupled to cell function, with morphological changes to mitochondria accompanying a multitude of processes as diverse as cell pluripotency, division, differentiation, senescence and death. Accordingly, disturbed dynamics of mitochondrial membranes are linked to severe human disorders.

    • Marta Giacomello
    • , Aswin Pyakurel
    • , Christina Glytsou
    •  & Luca Scorrano
  • Review Article |

    During cell division, the distribution of membrane-bound organelles needs to be tightly regulated to ensure the proper composition and function of daughter cells. Recent studies have shed light on the range of complex and dynamic mechanisms needed to mediate organelle inheritance and membrane remodelling during cell division.

    • Jeremy G. Carlton
    • , Hannah Jones
    •  & Ulrike S. Eggert
  • Review Article |

    Mammalian genomes generate long non-coding RNAs, which are degraded by the RNA surveillance machinery. This regulated degradation is vital for various processes, including for genome integrity, stem cell pluripotency and immune cell activation. Consequently, defects in RNA surveillance cause human diseases and developmental disorders.

    • Lekha Nair
    • , Hachung Chung
    •  & Uttiya Basu
  • Review Article |

    Ageing is characterized by the functional decline of tissues and organs and increased risk of ageing-associated disorders, and this decline is associated with epigenetic changes. Recently, ‘rejuvenating’ interventions, such as metabolic manipulation, partial cell reprogramming, heterochronic parabiosis and senescent cell ablation, have been proposed to extend healthspan and lifespan by modulating the epigenome.

    • Weiqi Zhang
    • , Jing Qu
    • , Guang-Hui Liu
    •  & Juan Carlos Izpisua Belmonte
  • Review Article |

    The mTOR pathway integrates diverse environmental cues to control biomass accumulation and metabolism by modulating key cellular processes, including protein synthesis and autophagy. Dysregulation of mTOR signalling has been implicated in metabolic disorders, neurodegeneration, cancer and ageing, and is thus a promising target for pharmacological intervention.

    • Grace Y. Liu
    •  & David M. Sabatini
  • Review Article |

    Cholesterol is an important structural component of all animal cell membranes that functions in various processes, including membrane dynamics and cell signalling, and is also a precursor of other molecules. Deregulation of cholesterol metabolism — biosynthesis, dietary absorption and cellular uptake, storage and efflux — is linked to many diseases, including cardiovascular and genetic diseases, and cancer. A better understanding of cholesterol metabolism offers the possibility to control systemic cholesterol levels to improve human health.

    • Jie Luo
    • , Hongyuan Yang
    •  & Bao-Liang Song
  • Review Article |

    Animal circadian rhythms are controlled by central and peripheral molecular clocks, whose components generate oscillations in their own abundance and activity. Insights into how these clocks time the function of organs and tissues is increasing our understanding of animal physiology.

    • Alina Patke
    • , Michael W. Young
    •  & Sofia Axelrod
  • Review Article |

    Lysosomes are mainly associated with cellular waste disposal. But it has recently been discovered that by integrating various environmental cues, they have a broader role as regulatory hubs for cellular and organismal homeostasis. The modulation of lysosome function could thus be a promising therapeutic strategy for the treatment of cancer as well as metabolic and neurodegenerative disorders.

    • Andrea Ballabio
    •  & Juan S. Bonifacino
  • Review Article |

    AAA+ proteins are macromolecular machines that remodel a vast array of cellular substrates, including protein aggregates, macromolecular complexes and polymers. Recent advances in cryo-electron microscopy have enabled visualization of them while in action, leading to a better understanding of the mechanisms of engagement and processing of their diverse substrates.

    • Cristina Puchades
    • , Colby R. Sandate
    •  & Gabriel C. Lander
  • Review Article |

    Although organelles compartmentalize eukaryotic cells, they can communicate and integrate their activities by connecting at membrane contact sites (MCSs). The roles of MCSs in biology are becoming increasingly clear, with MCSs now known to function in intracellular signalling, lipid metabolism, membrane dynamics, organelle biogenesis and the cellular stress response.

    • William A. Prinz
    • , Alexandre Toulmay
    •  & Tamas Balla
  • Review Article |

    Endosomal sorting complexes required for transport (ESCRTs) are key membrane remodellers, which drive the budding, scission and sealing of various cellular membranes. Accordingly, ongoing research focuses on how ESCRTs mediate a wide-range of cellular processes, including cytokinesis, endosome maturation, autophagy, membrane repair and viral replication.

    • Marina Vietri
    • , Maja Radulovic
    •  & Harald Stenmark
  • Review Article |

    Novel methods for tracking the progeny of single cells involve prospective lineage tracing, in which DNA barcodes are introduced into single cells and tracked over time, or retrospective lineage tracing, in which somatic mutations are used as DNA barcodes. These methods improve our understanding of cell fates in development, cell differentiation and tissue regeneration.

    • Chloé S. Baron
    •  & Alexander van Oudenaarden
  • Review Article |

    Mitochondria are key executioners of apoptosis. However, it has recently become clear that beyond driving apoptosis, mitochondria also contribute to pro-inflammatory signalling and other types of regulated cell death. These functions are relevant to disease and could be targeted in the treatment of, for example, degenerative disorders, infection and cancer.

    • Florian J. Bock
    •  & Stephen W. G. Tait
  • Review Article |

    When cells migrate through complex 3D environments, as are most tissues, they encounter several challenges, including the need to adapt to changing biomechanical properties of the surroundings, squeezing through narrow passages and coordinating motion with other cells. A better understanding of 3D cell migration mechanisms provides key insights into development, tissue regeneration, immune responses and cancer cell dissemination.

    • Kenneth M. Yamada
    •  & Michael Sixt
  • Review Article |

    Transcription-blocking DNA lesions (TBLs) cause transcription stress and are repaired by transcription-coupled nucleotide excision repair (TC-NER). TBL detection by the stalling of RNA polymerase II is highly efficient but may interfere with repair, and overall with transcription and replication. Consequently, TC-NER deregulation causes hereditary disorders with complex genotype–phenotype correlations.

    • Hannes Lans
    • , Jan H. J. Hoeijmakers
    • , Wim Vermeulen
    •  & Jurgen A. Marteijn
  • Review Article |

    N6-methyladenosine (m6A) is the most abundant mRNA internal modification. The recent mapping of m6A has provided insights into which and how mRNAs are modified, how m6A affects gene expression and how it is linked to cellular differentiation, cancer progression and other biological processes.

    • Sara Zaccara
    • , Ryan J. Ries
    •  & Samie R. Jaffrey
  • Review Article |

    Different genomic regions are replicated at different times during the S phase of the cell cycle, forming early- and late-replicating domains that occupy different locations in the nucleus. The recent identification of specific DNA sequences and long non-coding RNAs that regulate DNA replication timing is providing key insights into the roles of replication timing and into timing and 3D organization.

    • Claire Marchal
    • , Jiao Sima
    •  & David M. Gilbert
  • Review Article |

    Predicting how proteins fold enables inferring their function. Conversely, rational protein design allows for engineering novel protein functionalities. Recent improvements in computational algorithms and technological advances have dramatically increased the accuracy and speed of protein structure modelling, providing novel opportunities for controlling protein function, with potential applications in biomedicine, industry and research.

    • Brian Kuhlman
    •  & Philip Bradley
  • Review Article |

    DNA methylation is essential for mammalian embryogenesis owing to its repression of transposons and genes, but it is also associated with gene activation. The recent use of sensitive technologies has revealed that DNA methylation dynamics vary considerably between embryonic, germline and somatic cell development, with implications for genetic diseases and cancer.

    • Maxim V. C. Greenberg
    •  & Deborah Bourc’his
  • Review Article |

    The methylation of arginine residues regulates gene expression, DNA repair, growth factor signalling and liquid–liquid phase separation. Targeting this modification can thus be therapeutically relevant and inhibitors of arginine methylation are being tested in clinical trials, especially for neurodegenerative diseases and cancer.

    • Ernesto Guccione
    •  & Stéphane Richard
  • Review Article |

    The dynamic methylation of chromatin components — DNA, histones and RNA — is crucial in development, ageing and cancer. Therapies that target regulators of DNA and histone methylation in cancer have recently been developed. These promising therapies, which include strategies that may improve tumour immune surveillance, are already being tested in early-phase clinical trials.

    • Ewa M. Michalak
    • , Marian L. Burr
    • , Andrew J. Bannister
    •  & Mark A. Dawson
  • Review Article |

    Histone methylation regulates gene expression throughout animal development, governing processes as diverse as cell fate decisions, lineage specification, body patterning and organogenesis. Better understanding of the complex, context-specific roles of histone methylation in development will shed new light on the aetiology of developmental disorders.

    • Ashwini Jambhekar
    • , Abhinav Dhall
    •  & Yang Shi
  • Review Article |

    The choice between the major DNA double-strand break repair pathways is important for maintaining genomic stability. In mammals, selecting one pathway over another involves a complex series of binary ‘decisions’. Emerging evidence suggests that the ‘decision tree’ governing repair-pathway choice at stalled replication forks differs from that of replication-independent double-strand breaks.

    • Ralph Scully
    • , Arvind Panday
    • , Rajula Elango
    •  & Nicholas A. Willis
  • Review Article |

    The Hsp70 chaperones regulate protein metabolism, including folding, unfolding, subcellular localization, aggregation/disaggregation and incorporation into protein complexes. Recent studies have revealed the mechanisms of functions of Hsp70s and their co-chaperones, highlighting new opportunities for modulating disease-related Hsp70 roles.

    • Rina Rosenzweig
    • , Nadinath B. Nillegoda
    • , Matthias P. Mayer
    •  & Bernd Bukau
  • Review Article |

    The respiratory system comprises multiple cell types, and consequently its development and regeneration involves intricate cellular crosstalk. Better understanding of these complex cellular interactions will improve the treatment of respiratory diseases and tissue repair after injury.

    • Jarod A. Zepp
    •  & Edward E. Morrisey
  • Review Article |

    The 3D organization of the genome is crucial for gametogenesis, embryogenesis and cell differentiation through its modulation of transcription, DNA replication and cell division. Recent studies have highlighted the roles of 3D chromatin dynamics, such as the formation of enhancer–promoter interactions in mammalian development.

    • Hui Zheng
    •  & Wei Xie
  • Review Article |

    The functions of many regulatory RNAs depend on how their 3D structure changes in response to cellular conditions. Recent studies have revealed that RNA exists as a dynamic ensemble of conformations, which form with different probabilities in different cellular conditions and thus modulate RNA function.

    • Laura R. Ganser
    • , Megan L. Kelly
    • , Daniel Herschlag
    •  & Hashim M. Al-Hashimi
  • Review Article |

    Integrin extracellular matrix receptors establish contacts between the cell interior and the cell microenvironment. Integrins are subjected to complex biochemical and mechanical regulation, which allows cells to respond to extracellular matrix with different physicochemical properties and fine-tunes cell behaviour.

    • Jenny Z. Kechagia
    • , Johanna Ivaska
    •  & Pere Roca-Cusachs
  • Review Article |

    CRISPR–Cas systems have revolutionized genome editing, and the CRISPR–Cas toolkit has been expanding to include single-base editing enzymes, targeting RNA and fusing inactive Cas proteins to effectors that regulate various nuclear processes. Consequently, CRISPR–Cas systems are being tested for gene and cell therapies.

    • Adrian Pickar-Oliver
    •  & Charles A. Gersbach
  • Review Article |

    Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that generate 3-phosphoinositides, which govern cellular signal transduction and membrane trafficking. The PI3K family comprises three classes of enzymes, which include several isoforms and complexes; the myriad of cellular functions and means of regulation of these enzymes are now coming into focus.

    • Benoit Bilanges
    • , York Posor
    •  & Bart Vanhaesebroeck
  • Review Article |

    Nonsense-mediated mRNA decay (NMD) is a quality and quantity control mechanism for degrading mutated mRNAs to protect the integrity of the transcriptome and proteome and unmutated mRNAs to control their quantity. NMD dysfunction in humans is associated with intellectual disability and cancer.

    • Tatsuaki Kurosaki
    • , Maximilian W. Popp
    •  & Lynne E. Maquat
  • Review Article |

    Cellular metabolism is rewired in proliferating cells to support their increased need for macromolecule biosynthesis. A better understanding of how cells utilize nutrients for biosynthetic pathways and how they overcome the metabolic challenges associated with high proliferation rates can lead to better control of cell proliferation and improved cancer treatments.

    • Jiajun Zhu
    •  & Craig B. Thompson
  • Review Article |

    Cilia, and primary cilia in particular, are important signalling organelles with established roles in odorant, light and Hedgehog morphogen signal transduction. Cilia are enriched in signalling receptors and effectors and in specific lipids. Addressing how this unique composition is established and maintained is key to understanding cell signalling.

    • Maxence V. Nachury
    •  & David U. Mick
  • Review Article |

    Components of the ribosome-associated protein quality control (RQC) pathway recognize truncated proteins resulting from the stalling of ribosomes on mRNAs during translation and target them for degradation. Defects in RQC can lead to disease, and recent insights have revealed RQC mechanisms in the cytosol and on mitochondria and the endoplasmic reticulum that involve the E3 ligase listerin and/or the formation of carboxy-terminal alanine and threonine tails.

    • Claudio A. P. Joazeiro
  • Review Article |

    Genome organization can regulate gene expression, but can gene expression regulate genome organization? Recent studies reveal that, although not required for higher-level genome organization, transcription has a role in the formation and stabilization of genomic subdomains and enhancer–promoter interactions.

    • Bas van Steensel
    •  & Eileen E. M. Furlong
  • Review Article |

    Following DNA damage, the transcription factor p53 determines whether cells undergo apoptosis or cell cycle arrest and DNA repair. To enable different cellular outcomes, p53 is regulated through its temporal expression dynamics and post-translational modification, and by interactions with chromatin, chromatin regulators and transcription factors.

    • Antonina Hafner
    • , Martha L. Bulyk
    • , Ashwini Jambhekar
    •  & Galit Lahav
  • Review Article |

    Metabolites can actively regulate biological processes and may directly modulate phenotype. The current challenge of metabolomics is to provide a platform for the discovery of such bioactive metabolites and — in combination with other omics technologies — to determine their biological functions.

    • Markus M. Rinschen
    • , Julijana Ivanisevic
    • , Martin Giera
    •  & Gary Siuzdak
  • Review Article |

    The haematopoietic stem cell (HSC) niche in the bone marrow ensures haematopoiesis by regulating the function of HSCs and progenitor cells. An improved understanding of this regulation in homeostasis, ageing and cancer should aid the development of therapies to rejuvenate aged HSCs or niches and treat malignancies.

    • Sandra Pinho
    •  & Paul S. Frenette
  • Review Article |

    By opposing protein ubiquitylation, deubiquitylating enzymes (DUBs) regulate various cellular processes, including protein degradation, the DNA damage response, cell signalling and autophagy. Many DUBs show high specificity for ubiquitin chain architecture and/or the protein substrate that they recognize, and have emerged as exciting therapeutic targets within the field of proteostasis.

    • Michael J. Clague
    • , Sylvie Urbé
    •  & David Komander
  • Review Article |

    Misfolded proteins have a high propensity to form potentially toxic aggregates. Cells employ a complex network of processes, involving chaperones and proteolytic machineries that ensure proper protein folding and remodel or degrade misfolded species and aggregates. This proteostasis network declines with age, which can be linked to human degenerative diseases.

    • Mark S. Hipp
    • , Prasad Kasturi
    •  & F. Ulrich Hartl
  • Review Article |

    Spatial proteomics improves our understanding of protein function by revealing the subcellular localizations of proteins and their movement between compartments. This Review discusses spatial proteomics approaches, their successful application in cell biology and ways to improve integration of spatial proteomics data.

    • Emma Lundberg
    •  & Georg H. H. Borner
  • Review Article |

    BCL-2 family proteins are the mediators of apoptotic cell death. The balance between pro-apoptotic and pro-survival BCL-2 family members is differently regulated in various physiological contexts to modulate cellular apoptotic susceptibility. Perturbation of this balance causes excessive or insufficient cell death, leading to diseases such as neurodegeneration and cancer.

    • Rumani Singh
    • , Anthony Letai
    •  & Kristopher Sarosiek
  • Review Article |

    Circadian rhythms align organismal functions with phases of rest and activity. Accordingly, circadian oscillations occur in many physiological processes, including various metabolic functions. In turn, metabolic cues are emerging as regulators of the circadian clock. This crosstalk between metabolism and circadian rhythms has important implications for human health.

    • Hans Reinke
    •  & Gad Asher
  • Review Article |

    Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization and interactions. This Review discusses how the mitochondrial protein import machinery functions as a key organizer of these protein networks, its involvement in the formation of membrane contact sites, and how defects in protein import can lead to disease.

    • Nikolaus Pfanner
    • , Bettina Warscheid
    •  & Nils Wiedemann
  • Review Article |

    An increase in white adipose tissue is associated with obesity and reduced metabolic function. Interestingly, however, adipose tissue expansion through the generation of new adipocytes (adipogenesis), rather than through increasing adipocyte size, can prevent this metabolic decline. Thus, a better understanding of adipogenesis can inform new strategies to increase metabolic health in humans.

    • Alexandra L. Ghaben
    •  & Philipp E. Scherer
  • Review Article |

    The Hippo pathway effectors YAP and TAZ regulate normal and tumorigenic organ growth. Recent studies in vitro and in mouse models have shown that these two transcription co-activators can also promote tissue regeneration. This property could be exploited for regenerative medicine, as long as the therapeutic approaches can minimize the potential for cancer development.

    • Iván M. Moya
    •  & Georg Halder