DNA replication

  • Article
    | Open Access

    Replicative hexameric helicases are fundamental components of replisomes. Here the authors resolve a cryo-EM structure of the E1 helicase from papillomavirus bound to a DNA replication fork, providing insights into the mechanism of DNA unwinding by these hexameric enzymes.

    • Abid Javed
    • , Balazs Major
    •  & Elena V. Orlova
  • Article
    | Open Access

    RAD51 is a well known player of DNA repair and homologous recombination. Here the authors reveal a function for RAD51 in protecting under-replicated DNA in mitotic human cells, promoting mitotic DNA synthesis (MiDAS) and successful chromosome segregation.

    • Isabel E. Wassing
    • , Emily Graham
    •  & Fumiko Esashi
  • Article
    | Open Access

    The BRCA1-PALB2-BRCA2-RAD51 (BRCA1-P) complex is well known to play a fundamental role in DNA repair, but how the complex recruitment is regulated is still a matter of interest. Here the authors reveal mechanistic insights into RNF168 activity being responsible for PALB2 recruitment, through BARD1-BRCA1 during homologous recombination repair.

    • John J. Krais
    • , Yifan Wang
    •  & Neil Johnson
  • Article
    | Open Access

    Germline mutations in BRCA1 or BRCA2 tumour suppressor genes predispose to different cancers, as does oncogene activation. Here the authors reveal that aberrant transcription of specific genes triggered by activation of the oncogene β-catenin causes replication failure and cell death in the context of BRCA1/2 deficiency.

    • Rebecca A. Dagg
    • , Gijs Zonderland
    •  & Madalena Tarsounas
  • Perspective
    | Open Access

    A key feature of living cells is the cell cycle. In this Perspective, the authors explore attempts to recreate this process and what is still required for an integrated synthetic cell cycle.

    • Lorenzo Olivi
    • , Mareike Berger
    •  & John van der Oost
  • Article
    | Open Access

    Tpr nucleoporin is known to be essential for nuclear transport and mitosis processes. Here the authors explore the link between Tpr and genome instability providing insights into the role of Tpr in safeguarding cells from RNA-mediated replication stress.

    • Martin Kosar
    • , Michele Giannattasio
    •  & Marco Foiani
  • Article
    | Open Access

    Single-stranded DNA during DNA replication and repair in S/G2 needs protection by replication protein A (RPA). Here the authors reveal that RPA also shields inherited single-stranded DNA in G1, representing replication remnants from the previous cell cycle, to allow for post-mitotic DNA synthesis.

    • Aleksandra Lezaja
    • , Andreas Panagopoulos
    •  & Matthias Altmeyer
  • Article
    | Open Access

    BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.

    • Jekaterina Vohhodina
    • , Liana J. Goehring
    •  & David M. Livingston
  • Article
    | Open Access

    DNA replication processes are often dysregulated in cancer. Here the authors analyse DNA synthesis patterns in cancer cells undergoing partial genome re-replication to reveal that re-replication exhibits aberrant replication fork dynamics and a skewed distribution of replication initiation that over-duplicates early-replicating genomic regions.

    • Haiqing Fu
    • , Christophe E. Redon
    •  & Mirit I. Aladjem
  • Article
    | Open Access

    Different proteins localised at telomeres ensure chromosome end stability to prevent double strand-end break recognition. Here the authors provide new insight into how in S. cerevisiae the interaction between Rif2 and Rad50 inhibits MRX functions at telomeres.

    • Florian Roisné-Hamelin
    • , Sabrina Pobiega
    •  & Stéphane Marcand
  • Article
    | Open Access

    In the genome, repetitive guanine-rich sequences have the potential to spontaneously fold into non-canonical DNA secondary structures known as G-quadruplex (G4). Using novel single-molecule imaging approaches, the authors reveal that G4 formation within active replication forks locally perturb replisome dynamics and damage response signaling, which require RPA and FANCJ for regulation.

    • Wei Ting C. Lee
    • , Yandong Yin
    •  & Eli Rothenberg
  • Article
    | Open Access

    Eukaryotic DNA replication is regulated to ensure copying of the genome (only) once per cell cycle. Here the authors, using optical trapping and confocal microscopy, demonstrate the dynamics of the origin recognition complex and subsequent intermediates that lead up to the loading of an MCM helicase onto DNA.

    • Humberto Sánchez
    • , Kaley McCluskey
    •  & Nynke H. Dekker
  • Article
    | Open Access

    During pre-Replication Complex, eukaryotic cells load two MCMs into a head-to-head Double Hexamer around duplex DNA (DH). Here the authors preRC assembly assay with purified proteins to reveal insights into S. cerevisiae’s first steps that lead to the DH formation.

    • Marina Guerrero-Puigdevall
    • , Narcis Fernandez-Fuentes
    •  & Jordi Frigola
  • Article
    | Open Access

    Most regions of the mammalian genome replicate both alleles in a synchronous manner, but some loci have been found to replicate asynchronously and the time of replication of each allele is different. Here the authors, by employing clonal mouse cells from a hybrid strain chart replication timing over the entire genome, using polymorphisms to distinguish between the paternal and maternal alleles.

    • Britny Blumenfeld
    • , Hagit Masika
    •  & Itamar Simon
  • Article
    | Open Access

    Replication forks that are stalled at obstacles on the DNA template can be restarted by homologous recombination. Here, the authors show replication dynamics during homologous recombination-dependent replication fork restart by combining polymerase usage sequencing and a Monte Carlo mathematical model.

    • Karel Naiman
    • , Eduard Campillo-Funollet
    •  & Antony M. Carr
  • Article
    | Open Access

    The BLM helicase interacts with the topoisomerase TOP3A and RMI1 to form the BTR complex. Here, the authors reveal that this complex contains multiple binding sites for the single-stranded DNA-binding complex RPA, and that RPA-binding stimulates BLM recruitment to stalled replication forks to promote their restart after replication stress.

    • Ann-Marie K. Shorrocks
    • , Samuel E. Jones
    •  & Andrew N. Blackford
  • Article
    | Open Access

    Rad5 is a hub connecting three replication stress tolerance pathways. Here, the authors present the 3.3 Å crystal structure of a N-terminal truncated K.lactis Rad5 construct that reveals the spatial arrangement of the HIRAN, Snf2 and RING domains and structure-guided in vitro and in vivo experiments reveal multiple activities of the yeast Rad5 HIRAN domain among them a role in binding PCNA and supporting its ubiquitination.

    • Miaomiao Shen
    • , Nalini Dhingra
    •  & Song Xiang
  • Article
    | Open Access

    The role of cohesin in organizing a functional nuclear architecture remains poorly understood. Here the authors show that cohesin depleted cells pass through endomitosis forming a multilobulated nucleus able to proceed through S-phase with typical features of active and inactive nuclear compartments and spatio-temporal patterns of replication domains.

    • Marion Cremer
    • , Katharina Brandstetter
    •  & Thomas Cremer
  • Article
    | Open Access

    The fork protection complex (FPC), including the proteins TIMELESS and TIPIN, stabilizes the replisome to ensure unperturbed fork progression during DNA replication. Here the authors reveal that that SDE2, a PCNA-associated protein, plays an important role in maintaining active replication and protecting stalled forks by regulating the replication fork protection complex (FPC).

    • Julie Rageul
    • , Jennifer J. Park
    •  & Hyungjin Kim
  • Article
    | Open Access

    In high fidelity DNA polymerases the exonuclease site is distal from the polymerization site and it is unknown how the primer strand travels between the two sites when mis-incorporated nucleotides must be removed. Here, the authors perform MD simulations and identify an optimal path for DNA primer strand translocation in the E. coli replicative DNA polymerase III and characterise the kinetics and dynamics of the Pol III pol-to-exo mode transition, which is validated with mutagenesis experiments.

    • Thomas Dodd
    • , Margherita Botto
    •  & Ivaylo Ivanov
  • Article
    | Open Access

    Telomerase enzymes add telomeric repeats to the end of linear chromosomes. Here the authors reveal mechanisms by which oxidized dNTPs and therapeutic dNTPs inhibit telomerase-mediated telomere elongation.

    • Samantha L. Sanford
    • , Griffin A. Welfer
    •  & Patricia L. Opresko
  • Article
    | Open Access

    Contrary to most eukaryotes that lack sequence-specific origins of replication, S. cerevisiae origins are defined by specific DNA sequence motifs. Here the authors reveal that multiple subunits of ORC, including Orc2 and Orc4, contribute to the sequence-specificity of origins in S. cerevisiae.

    • Y. Hu
    • , A. Tareen
    •  & B. Stillman
  • Article
    | Open Access

    Herpesviruses code for conserved protein kinases (CHPKs) that exert several regulatory functions by interacting with cellular factors. Here, the authors use affinity purification mass spectrometry (AP–MS) to identify differential interaction partners of CHPKs from seven different human herpesviruses, finding Cyclin A and associated factors as a specific signature of β-herpesvirus kinases.

    • Boris Bogdanow
    • , Max Schmidt
    •  & Lüder Wiebusch
  • Article
    | Open Access

    In mammalian cells, during transcription and replication, RNA:DNA hybrid structures known as R-loops can arise, posing as obstacles to replication fork progression. Here the authors reveal that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication associated DNA damage in cancer cells.

    • Lisa Prendergast
    • , Urszula L. McClurg
    •  & Manolis Papamichos-Chronakis
  • Article
    | Open Access

    A unique cell envelope contributes to the antibiotic resistance of the pathogen Acinetobacter baumannii. Here, Geisinger et al. identify A. baumannii mutants with altered antibiotic susceptibility, infer the function of uncharacterized proteins involved in envelope synthesis, and predict antibiotic synergies.

    • Edward Geisinger
    • , Nadav J. Mortman
    •  & Ralph R. Isberg
  • Article
    | Open Access

    The origin recognition complex (ORC) is essential for loading the Mcm2–7 replicative helicase onto DNA during DNA replication initiation. Here, the authors describe several cryo-electron microscopy structures of Drosophila ORC bound to DNA and its cofactor Cdc6 and also report an in vitro reconstitution system for Drosophila Mcm2–7 loading, revealing unexpected features of ORC’s DNA binding and remodeling mechanism during Mcm2–7 loading.

    • Jan Marten Schmidt
    •  & Franziska Bleichert
  • Article
    | Open Access

    Whereas the toxic effects of ethanol are well-documented, the underlying mechanism is obscure. This study uses the eukaryotic model S. cerevisiae to reveal how exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate.

    • Karin Voordeckers
    • , Camilla Colding
    •  & Kevin J. Verstrepen
  • Article
    | Open Access

    Common fragile sites are regions susceptible to replication stress and are prone to chromosomal instability. Here, the authors, by analyzing the contribution of 3D chromatin organization, identify and characterize a fragility signature and precisely map these fragility regions.

    • Dan Sarni
    • , Takayo Sasaki
    •  & Batsheva Kerem
  • Article
    | Open Access

    Replication stress has been associated with transient remodelling of replication intermediates into reversed forks, followed by efficient fork restart. Here the authors systematically analyse the role of RAD51 paralogs in these transactions, providing insights on the mechanistic role of different complexes of these proteins.

    • Matteo Berti
    • , Federico Teloni
    •  & Massimo Lopes
  • Article
    | Open Access

    DNA replication is tightly regulated during S phase of the cell cycle to ensure timely and accurate genome duplication. Here, the authors reveal that E2F-dependent transcription determines the maximal amount of DNA a cell is able to synthesise per unit time throughout S phase.

    • Betheney R. Pennycook
    • , Eva Vesela
    •  & Robertus A. M. de Bruin
  • Article
    | Open Access

    How chromosome replication and segregation is organised in E. coli is a matter of debate. Here the authors visualise the bacterial chromosome and the replisomes during DNA replication, providing support for a previously suggested train track model.

    • Aleksandre Japaridze
    • , Christos Gogou
    •  & Cees Dekker
  • Article
    | Open Access

    In the S phase of the cell cycle, the full genome needs to be replicated before cell division occurs. Here, authors show that in budding yeast DNA synthesis is completed after chromosome segregation begins.

    • Tsvetomira Ivanova
    • , Michael Maier
    •  & Manuel Mendoza
  • Article
    | Open Access

    Replicative DNA polymerases (DNAPs) have evolved the ability to copy the genome with high processivity and fidelity. Here, the authors present a cryo-EM structure of the DNA-bound PolD–PCNA complex from Pyrococcus abyssi to reveal the molecular basis for the interaction and cooperativity between a replicative DNAP and PCNA.

    • Clément Madru
    • , Ghislaine Henneke
    •  & Ludovic Sauguet