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Articles by Michael E. O’Donnell
Mechanistic diversity of clamp loading at small DNA gaps
JBC ReviewsArticles in Press113397Open access Affiliations & Notes 1Department of Structural Biology, Van Andel Institute, Grand Rapids, Michigan, United States of America 2DNA Replication Laboratory and Howard Hughes Medical Institute, The Rockefeller University, New York, New York, United States of America Article Info Publication History: Received May 20, 2026; Revised July 30, 2026; Accepted August 3, 2026; Published online August 10, 2026 DOI: 10.1016/j.jbc.2026.113397 External LinkAlso...
Dpb11 facilitates the colocalization of Mec1-Ddc2 with its activators on gapped DNA
Keywords: DNA damage response replication stress cell cycle checkpoint Mec1-Ddc2 ATR-ATRIP Dpb11 TopBP1 single-molecule microscopy Research topic(s) CP: molecular biology Introduction The DNA damage and replication stress checkpoint comprises crucial cellular responses for the maintenance of genome stability and prevention of carcinogenesis.1,2 This checkpoint can be triggered by single-stranded DNA (ssDNA) resulting from genotoxic challenges during the G1, S, or G2 phase of the cell cycle.
ATP is dispensable for E. coli DNA replication and eukaryotic helicase activity
Abstract Adenosine triphosphate (ATP) hydrolysis is the main cellular source of energy used to drive biochemical reactions that are otherwise energetically unfavourable. The chemical energy stored in phosphoanhydride bonds is released upon hydrolysis of ATP to ADP and is used to drive mechanical work and conformational change. DNA replication is a canonical process in which the multi-enzyme replisome is thought to rely on ATP hydrolysis for its function.
The E. coli DnaX clamp loader sharply bends DNA to load β-clamp at nicks and small gaps
ArticleVolume 86, Issue 11p2055-2069.e10Open access Affiliations & Notes 1Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA 2DNA Replication Laboratory and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA Article Info Publication History: Received June 18, 2025; Revised January 20, 2026; Accepted April 20, 2026; Published online May 14, 2026 DOI: 10.1016/j.molcel.2026.04.020 External LinkAlso available on ScienceDirect External Link...
A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis
Keywords DNA replication DNA damage sliding clamp clamp loader Okazaki fragment genome maintenance PCNA RFC FEN1 Polδ Introduction Genome replication across all domains of life requires DNA sliding clamps that couple with DNA polymerases to achieve processive DNA synthesis.1,2,3 In eukaryotes, this activity is fulfilled by proliferating cell nuclear antigen (PCNA), a homotrimer that forms a ring-shaped complex encircling double-stranded (ds) DNA.4,5 The closed-ring architecture of PCNA...
Molecular determinants of Smc5/6 association with DNA junctions - Nature Communications
Abstract Smc5/6 is an essential genome maintenance complex that interacts with double-stranded (ds) DNA, single-stranded (ss) DNA, and ss-dsDNA junctions. DNA association underlies Smc5/6’s functions in managing intermediates generated during genome replication and repair. However, the mechanisms of this activity are not fully understood. Here, we report a single-molecule study examining Smc5/6 association with a dsDNA substrate containing a ssDNA gap with defined 3’ and 5’ junctions.
The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme
L. D. Langston, M. O’Donnell, DNA replication: Keep moving and don’t mind the gap. Mol. Cell. 23, 155–160 (2006). A. Johnson, M. O’Donnell, Cellular DNA replicases: Components and dynamics at the replication fork. Annu. Rev. Biochem. 74, 283–315 (2005). Z. F. Pursell, I. Isoz, E.-B. Lundström, E. Johansson, T. A. Kunkel, Yeast DNA polymerase ε participates in leading-strand DNA replication. Science 317, 127–130 (2007). T. A. Kunkel, P. M.
Author Correction: Structures of the human leading strand Polε–PCNA holoenzyme - Nature Communications
Correction to: Nature Communications https://doi.org/10.1038/s41467-024-52257-x, published online 08 September 2024 In the original version of the published article, the Supplementary Information was missing Supplementary Fig. 9. This has now been replaced.
DNA polymerase ζ has robust reverse transcriptase activity relative to other cellular DNA polymerases.
Keywords DNA polymerase zeta reverse transcriptase translesion DNA polymerase double-strand DNA break repair DNA synthesis Introduction DNA damage plagues all cell types. Damage comes in the form of any alteration in DNA structure leading to a change in coding capacity or deterioration of genome integrity.
Retraction Note: High replicability of newly discovered social-behavioural findings is achievable - Nature Human Behaviour
Retraction to: Nature Human Behaviour (2023) 8:311-319 https://doi.org/10.1038/s41562-023-01749-9 The Editors are retracting this article following concerns initially raised by Bak-Coleman and Devezer1.
Structures of the human leading strand Polε–PCNA holoenzyme - Nature Communications
Abstract In eukaryotes, the leading strand DNA is synthesized by Polε and the lagging strand by Polδ. These replicative polymerases have higher processivity when paired with the DNA clamp PCNA. While the structure of the yeast Polε catalytic domain has been determined, how Polε interacts with PCNA is unknown in any eukaryote, human or yeast. Here we report two cryo-EM structures of human Polε–PCNA–DNA complex, one in an incoming nucleotide bound state and the other in a nucleotide exchange state.
The human ATAD5 has evolved unique structural elements to function exclusively as a PCNA unloader - Nature Structural & Molecular Biology
Abstract Humans have three different proliferating cell nuclear antigen (PCNA) clamp-loading complexes: RFC and CTF18-RFC load PCNA onto DNA, but ATAD5-RFC can only unload PCNA from DNA. The underlying structural basis of ATAD5-RFC unloading is unknown.
Autoinhibition of a clamp-loader ATPase revealed by deep mutagenesis and cryo-EM - Nature Structural & Molecular Biology
Abstract Clamp loaders are AAA+ ATPases that facilitate high-speed DNA replication. In eukaryotic and bacteriophage clamp loaders, ATP hydrolysis requires interactions between aspartate residues in one protomer, present in conserved ‘DEAD-box’ motifs, and arginine residues in adjacent protomers. We show that functional defects resulting from a DEAD-box mutation in the T4 bacteriophage clamp loader can be compensated by widely distributed single mutations in the ATPase domain.
RETRACTED ARTICLE: High replicability of newly discovered social-behavioural findings is achievable - Nature Human Behaviour
Abstract Failures to replicate evidence of new discoveries have forced scientists to ask whether this unreliability is due to suboptimal implementation of methods or whether presumptively optimal methods are not, in fact, optimal. This paper reports an investigation by four coordinated laboratories of the prospective replicability of 16 novel experimental findings using rigour-enhancing practices: confirmatory tests, large sample sizes, preregistration and methodological transparency.
Structures of 9-1-1 DNA checkpoint clamp loading at gaps from start to finish and ramification on biology
Antibodies Anti-digoxigenin, fab fragments, sheep Roche Cat# 11214667001; RRID:AB_514494 Bacterial and virus strains E. coli DH5α competent cells Thermo Fisher Scientific Cat# 18265017 E.
Auditing the value of empirical audits | Proceedings of the National Academy of Sciences
Skip to main content Exact replication is impossible (1), but various approaches to “direct” and “conceptual” replication have been developed, including papers with multiple replications of a single study (2), large-scale efforts across multiple laboratories (3), and adversarial collaborations (4). Uniting these approaches is a set of best practices to ensure that published replications get the science right (5). The O’Donnell et al.
Smc5/6’s multifaceted DNA binding capacities stabilize branched DNA structures - Nature Communications
The three eukaryotic SMC complexes play different roles in genome organization and maintenance. Previous studies have suggested that Smc5/6 influences multiple processes required for genomic stability and some of its roles pertain to the management of impaired replication forks and joint DNA structures generated during DNA repair2. Both types of DNA substrates contain junction DNA consisting of ssDNA adjacent to dsDNA regions.
Empirical audit and review and an assessment of evidentiary value in research on the psychological consequences of scarcity
Abstract Empirical audit and review is an approach to assessing the evidentiary value of a research area. It involves identifying a topic and selecting a cross-section of studies for replication. We apply the method to research on the psychological consequences of scarcity.
Tennis Anyone? Learn more about writing craft at Virginia Highlands Festival
Tennis Anyone? Learn more about writing craft at Virginia Highlands Festival Joe Tennis | Tennis Anyone? Writers’ Day at this year’s Virginia Highlands Festival provides opportunities to learn from regionally and nationally renowned authors about the craft of writing. It’s an event for writers of all stripes — not just serious scribes. Look for the event on July 30 — Friday. Registration starts at 8 a.m. at the Southwest Virginia Higher Education Center, just off I-81’s Exit 14.
Structure of eukaryotic DNA polymerase δ bound to the PCNA clamp while encircling DNA
Significance The structure of the eukaryotic chromosomal replicase, DNA polymerase (Pol) δ, was determined in complex with its cognate proliferating cell nuclear antigen (PCNA) sliding clamp on primed DNA. The results show that the Pol3 catalytic subunit binds atop the PCNA ring, and the two regulatory subunits of Pol δ, Pol31, and Pol32, are positioned off to the side of the Pol3 clamp. The catalytic Pol3 binds DNA and PCNA such as to thread the DNA straight through the circular PCNA clamp.
Structure of the polymerase ε holoenzyme and atomic model of the leading strand replisome
Abstract The eukaryotic leading strand DNA polymerase (Pol) ε contains 4 subunits, Pol2, Dpb2, Dpb3 and Dpb4. Pol2 is a fusion of two B-family Pols; the N-terminal Pol module is catalytic and the C-terminal Pol module is non-catalytic. Despite extensive efforts, there is no atomic structure for Pol ε holoenzyme, critical to understanding how DNA synthesis is coordinated with unwinding and the DNA path through the CMG helicase-Pol ε-PCNA clamp.
DNA unwinding mechanism of a eukaryotic replicative CMG helicase
Abstract High-resolution structures have not been reported for replicative helicases at a replication fork at atomic resolution, a prerequisite to understanding the unwinding mechanism. The eukaryotic replicative CMG (Cdc45, Mcm2-7, GINS) helicase contains a Mcm2-7 motor ring, with the N-tier ring in front and the C-tier motor ring behind. The N-tier ring is structurally divided into a zinc finger (ZF) sub-ring followed by the oligosaccharide/oligonucleotide-binding (OB) fold ring.
Replication Fork Activation Is Enabled by a Single-Stranded DNA Gate in CMG Helicase
Highlights • Eukaryotic CMG helicase employs a gate in its ring to switch between ss and dsDNA • Gating enables CMG to vacate a replication fork when uncoupled from DNA polymerase • CMG diffuses on dsDNA and uses this gate to enter a fork and restart replication • Mcm10, an essential replisome factor, tethers CMG to DNA during the gating process Summary The eukaryotic replicative helicase CMG is a closed ring around double-stranded (ds)DNA at origins yet must transition to single-stranded...
The ring-shaped hexameric helicases that function at DNA replication forks
Georgescu, R. et al. Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proc. Natl. Acad. Sci. USA 114, E697–E706 (2017). This study reports a high-resolution structure of S. cerevisiae CMG at a replication fork and shows that CMG is oriented on DNA in a direction opposite to that predicted by conventional models. Yuan, Z. et al. Structure of the eukaryotic replicative CMG helicase suggests a pumpjack motion for translocation. Nat.
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