Show notes

How Your Cells Copy 6 Billion Letters of DNA (DNA Replication Animation)

How does a cell copy its DNA, and why is one of the two new strands made backwards, in pieces? This animation follows copying from the moment two helicases leave an origin: each fork's first primer is carried back across the origin to become the other fork's continuous strand, and then the backwards strand is made in fragments.

The video is coming soon to the channel.

Chapters

• 0:00 Intro: how much DNA you copy
• 1:24 Why copying starts in many places
• 1:59 Starting at an origin
• 3:14 The copying machinery
• 5:59 The leading strand
• 7:20 The lagging strand and Okazaki fragments
• 8:15 Removing the primers, sealing the nicks
• 9:22 The whole replication fork
• 9:53 When two forks meet
• 10:54 Semiconservative replication
• 11:26 The chromosome end problem
• 12:21 Every cell, every day
• 12:54 Open questions

Sources

69 sources. Each was checked against its record (Crossref, PubMed, the Protein Data Bank, or the textbook edition) and against the claim it supports.

Textbooks and books

• Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell, 4th edition. New York: Garland Science. Sections "DNA Replication Mechanisms" (www.ncbi.nlm.nih.gov/books/NBK26850/) and "The Initiation and Completion of DNA Replication in Chromosomes" (www.ncbi.nlm.nih.gov/books/NBK26826/). NCBI Bookshelf: www.ncbi.nlm.nih.gov/books/NBK21054/
• Clark MA, Choi J, Douglas M (2018). Biology 2e. OpenStax, Rice University. ISBN 9781947172524. openstax.org/details/books/biology-2e (accessed 2026-10-20)
• MacNeill S (2012). Composition and Dynamics of the Eukaryotic Replisome: A Brief Overview. In: MacNeill S (ed.), The Eukaryotic Replisome: a Guide to Protein Structure and Function. Subcell Biochem 62:1–17. Springer Netherlands. doi.org/10.1007/978-94-007-4572-8_1

Papers · Scale and numbers (the opening)

• Sender R, Milo R (2021). The distribution of cellular turnover in the human body. Nat Med 27:45–48. doi.org/10.1038/s41591-020-01182-9
• Nurk S, Koren S, Rhie A, et al. (2022). The complete sequence of a human genome. Science 376:44–53. doi.org/10.1126/science.abj6987
• Watson JD, Crick FH (1953). Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature 171:737–738. doi.org/10.1038/171737a0
• Whitman WB, Coleman DC, Wiebe WJ (1998). Prokaryotes: the unseen majority. Proc Natl Acad Sci U S A 95:6578–6583. doi.org/10.1073/pnas.95.12.6578
• Rodríguez-Gijón A, Nuy JK, Mehrshad M, et al. (2022). A Genomic Perspective Across Earth's Microbiomes Reveals That Genome Size in Archaea and Bacteria Is Linked to Ecosystem Type and Trophic Strategy. Front Microbiol 12:761869. doi.org/10.3389/fmicb.2021.761869
• Jackson DA, Pombo A (1998). Replicon clusters are stable units of chromosome structure: evidence that nuclear organization contributes to the efficient activation and propagation of S phase in human cells. J Cell Biol 140:1285–1295. doi.org/10.1083/jcb.140.6.1285
• Greenberg A, Simon I (2022). S Phase Duration Is Determined by Local Rate and Global Organization of Replication. Biology (Basel) 11:718. doi.org/10.3390/biology11050718
• Bialic M, Al Ahmad Nachar B, Koźlak M, Coulon V, Schwob E (2022). Measuring S-Phase Duration from Asynchronous Cells Using Dual EdU-BrdU Pulse-Chase Labeling Flow Cytometry. Genes (Basel) 13:408. doi.org/10.3390/genes13030408
• Méchali M (2010). Eukaryotic DNA replication origins: many choices for appropriate answers. Nat Rev Mol Cell Biol 11:728–738. doi.org/10.1038/nrm2976
• Theulot B, Lacroix L, Arbona JM, et al. (2022). Genome-wide mapping of individual replication fork velocities using nanopore sequencing. Nat Commun 13:3295. doi.org/10.1038/s41467-022-31012-0

Papers · Starting at an origin

• Remus D, Beuron F, Tolun G, Griffith JD, Morris EP, Diffley JF (2009). Concerted loading of Mcm2-7 double hexamers around DNA during DNA replication origin licensing. Cell 139:719–730. doi.org/10.1016/j.cell.2009.10.015
• Evrin C, Clarke P, Zech J, et al. (2009). A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication. Proc Natl Acad Sci U S A 106:20240–20245. doi.org/10.1073/pnas.0911500106
• Yeeles JT, Deegan TD, Janska A, Early A, Diffley JF (2015). Regulated eukaryotic DNA replication origin firing with purified proteins. Nature 519:431–435. doi.org/10.1038/nature14285
• Douglas ME, Ali FA, Costa A, Diffley JFX (2018). The mechanism of eukaryotic CMG helicase activation. Nature 555:265–268. doi.org/10.1038/nature25787
• Bell SP, Labib K (2016). Chromosome Duplication in Saccharomyces cerevisiae. Genetics 203:1027–1067. doi.org/10.1534/genetics.115.186452
• Fu YV, Yardimci H, Long DT, et al. (2011). Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell 146:931–941. doi.org/10.1016/j.cell.2011.07.045
• Georgescu R, Yuan Z, Bai L, et al. (2017). Structure of eukaryotic CMG helicase at a replication fork and implications to replisome architecture and origin initiation. Proc Natl Acad Sci U S A 114:E697–E706. doi.org/10.1073/pnas.1620500114

Papers · The replication fork

• Burgers PMJ, Kunkel TA (2017). Eukaryotic DNA Replication Fork. Annu Rev Biochem 86:417–438. doi.org/10.1146/annurev-biochem-061516-044709
• Nick McElhinny SA, Gordenin DA, Stith CM, Burgers PM, Kunkel TA (2008). Division of labor at the eukaryotic replication fork. Mol Cell 30:137–144. doi.org/10.1016/j.molcel.2008.02.022
• Johansson E, Dixon N (2013). Replicative DNA polymerases. Cold Spring Harb Perspect Biol 5:a012799. doi.org/10.1101/cshperspect.a012799
• Pellegrini L (2012). The Pol α-primase complex. Subcell Biochem 62:157–169. doi.org/10.1007/978-94-007-4572-8_9
• Jones ML, Aria V, Baris Y, Yeeles JTP (2023). How Pol α-primase is targeted to replisomes to prime eukaryotic DNA replication. Mol Cell 83:2911–2924.e16. doi.org/10.1016/j.molcel.2023.06.035
• Deng SK, Chen H, Symington LS (2015). Replication protein A prevents promiscuous annealing between short sequence homologies: Implications for genome integrity. Bioessays 37:305–313. doi.org/10.1002/bies.201400161
• Kim C, Paulus BF, Wold MS (1994). Interactions of human replication protein A with oligonucleotides. Biochemistry 33:14197–14206. doi.org/10.1021/bi00251a031
• Gaubitz C, Liu X, Pajak J, et al. (2022). Cryo-EM structures reveal high-resolution mechanism of a DNA polymerase sliding clamp loader. Elife 11:e74175. doi.org/10.7554/eLife.74175
• Stodola JL, Burgers PM (2016). Resolving individual steps of Okazaki-fragment maturation at a millisecond timescale. Nat Struct Mol Biol 23:402–408. doi.org/10.1038/nsmb.3207
• Balakrishnan L, Bambara RA (2013). Okazaki fragment metabolism. Cold Spring Harb Perspect Biol 5:a010173. doi.org/10.1101/cshperspect.a010173
• Flood CL, Rodriguez GP, Bao G, Shockley AH, Kow YW, Crouse GF (2015). Replicative DNA polymerase δ but not ε proofreads errors in Cis and in Trans. PLoS Genet 11:e1005049. doi.org/10.1371/journal.pgen.1005049
• Smith DJ, Whitehouse I (2012). Intrinsic coupling of lagging-strand synthesis to chromatin assembly. Nature 483:434–438. doi.org/10.1038/nature10895
• Okazaki R, Okazaki T, Sakabe K, Sugimoto K, Sugino A (1968). Mechanism of DNA chain growth. I. Possible discontinuity and unusual secondary structure of newly synthesized chains. Proc Natl Acad Sci U S A 59:598–605. doi.org/10.1073/pnas.59.2.598
• Aria V, Yeeles JTP (2019). Mechanism of Bidirectional Leading-Strand Synthesis Establishment at Eukaryotic DNA Replication Origins. Mol Cell 73:199–211.e10. doi.org/10.1016/j.molcel.2018.10.019
• Garbacz MA, Lujan SA, Burkholder AB, et al. (2018). Evidence that DNA polymerase δ contributes to initiating leading strand DNA replication in Saccharomyces cerevisiae. Nat Commun 9:858. doi.org/10.1038/s41467-018-03270-4
• Shuman S (2009). DNA ligases: progress and prospects. J Biol Chem 284:17365–17369. doi.org/10.1074/jbc.R900017200
• Sallmyr A, Rashid I, Bhandari SK, Naila T, Tomkinson AE (2020). Human DNA ligases in replication and repair. DNA Repair (Amst) 93:102908. doi.org/10.1016/j.dnarep.2020.102908
• Yuan Z, Georgescu R, Schauer GD, O'Donnell ME, Li H (2020). Structure of the polymerase ε holoenzyme and atomic model of the leading strand replisome. Nat Commun 11:3156. doi.org/10.1038/s41467-020-16910-5
• Leipe DD, Aravind L, Koonin EV (1999). Did DNA replication evolve twice independently? Nucleic Acids Res 27:3389–3401. doi.org/10.1093/nar/27.17.3389

Papers · When forks meet, and chromosome ends

• Dewar JM, Budzowska M, Walter JC (2015). The mechanism of DNA replication termination in vertebrates. Nature 525:345–350. doi.org/10.1038/nature14887
• Low E, Chistol G, Zaher MS, Kochenova OV, Walter JC (2020). The DNA replication fork suppresses CMG unloading from chromatin before termination. Genes Dev 34:1534–1545. doi.org/10.1101/gad.339739.120
• Zhou ZX, Lujan SA, Burkholder AB, Garbacz MA, Kunkel TA (2019). Roles for DNA polymerase δ in initiating and terminating leading strand DNA replication. Nat Commun 10:3992. doi.org/10.1038/s41467-019-11995-z
• Jenkyn-Bedford M, Jones ML, Baris Y, et al. (2021). A conserved mechanism for regulating replisome disassembly in eukaryotes. Nature 600:743–747. doi.org/10.1038/s41586-021-04145-3
• Dewar JM, Low E, Mann M, Räschle M, Walter JC (2017). CRL2(Lrr1) promotes unloading of the vertebrate replisome from chromatin during replication termination. Genes Dev 31:275–290. doi.org/10.1101/gad.291799.116
• Deegan TD, Mukherjee PP, Fujisawa R, Polo Rivera C, Labib K (2020). CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold. Elife 9:e60371. doi.org/10.7554/eLife.60371
• van den Boom J, Meyer H (2018). VCP/p97-Mediated Unfolding as a Principle in Protein Homeostasis and Signaling. Mol Cell 69:182–194. doi.org/10.1016/j.molcel.2017.10.028
• Dewar JM, Walter JC (2017). Mechanisms of DNA replication termination. Nat Rev Mol Cell Biol 18:507–516. doi.org/10.1038/nrm.2017.42
• Shintomi K, Hirano T (2010). Sister chromatid resolution: a cohesin releasing network and beyond. Chromosoma 119:459–467. doi.org/10.1007/s00412-010-0271-z
• Meselson M, Stahl FW (1958). The replication of DNA in Escherichia coli. Proc Natl Acad Sci U S A 44:671–682. doi.org/10.1073/pnas.44.7.671
• Chow TT, Zhao Y, Mak SS, Shay JW, Wright WE (2012). Early and late steps in telomere overhang processing in normal human cells: the position of the final RNA primer drives telomere shortening. Genes Dev 26:1167–1178. doi.org/10.1101/gad.187211.112
• Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB (1992). Telomere end-replication problem and cell aging. J Mol Biol 225:951–960. doi.org/10.1016/0022-2836(92)90096-3
• Harley CB, Futcher AB, Greider CW (1990). Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460. doi.org/10.1038/345458a0

Protein structures

• PDB 7PFO: Core human replisome. Jones ML, Baris Y, Taylor MRG, Yeeles JTP (2021). Structure of a human replisome shows the organisation and interactions of a DNA replication machine. EMBO J 40:e108819. doi.org/10.15252/embj.2021108819 · doi.org/10.2210/pdb7pfo/pdb
• PDB 8B9D: Human replisome bound by Pol Alpha. Jones ML, Aria V, Baris Y, Yeeles JTP (2023). Mol Cell 83:2911–2924.e16. doi.org/10.1016/j.molcel.2023.06.035 · doi.org/10.2210/pdb8b9d/pdb
• PDB 9F6D: Human DNA polymerase epsilon bound to DNA and PCNA (open conformation). Roske JJ, Yeeles JTP (2024). Structural basis for processive daughter-strand synthesis and proofreading by the human leading-strand DNA polymerase Pol ε. Nat Struct Mol Biol 31:1921–1931. doi.org/10.1038/s41594-024-01370-y · doi.org/10.2210/pdb9f6d/pdb
• PDB 6TNZ: Human polymerase delta-FEN1-PCNA toolbelt. Lancey C, Tehseen M, Raducanu VS, et al. (2020). Structure of the processive human Pol δ holoenzyme. Nat Commun 11:1109. doi.org/10.1038/s41467-020-14898-6 · doi.org/10.2210/pdb6tnz/pdb
• PDB 6VVO: Structure of the human clamp loader (Replication Factor C, RFC) bound to the sliding clamp (Proliferating Cell Nuclear Antigen, PCNA). Gaubitz C, Liu X, Magrino J, et al. (2020). Structure of the human clamp loader reveals an autoinhibited conformation of a substrate-bound AAA+ switch. Proc Natl Acad Sci U S A 117:23571–23580. doi.org/10.1073/pnas.2007437117 · doi.org/10.2210/pdb6vvo/pdb (the PDB record still lists the bioRxiv preprint; the PNAS paper reports 6VVO)
• PDB 6P09: Human DNA Ligase 1 bound to an adenylated, dideoxy-terminated DNA nick. Tumbale PP, Jurkiw TJ, Schellenberg MJ, Riccio AA, O'Brien PJ, Williams RS (2019). Two-tiered enforcement of high-fidelity DNA ligation. Nat Commun 10:5431. doi.org/10.1038/s41467-019-13478-7 · doi.org/10.2210/pdb6p09/pdb
• PDB 4GOP: Structure and conformational change of a replication protein A heterotrimer bound to ssDNA (Ustilago maydis). Fan J, Pavletich NP (2012). Genes Dev 26:2337–2347. doi.org/10.1101/gad.194787.112 · doi.org/10.2210/pdb4gop/pdb
• PDB 8S0C: H. sapiens ORC1-5 bound to double-stranded DNA as part of the MCM-ORC complex; PDB 8S0E: H. sapiens OCCM bound to double-stranded DNA. Weissmann F, Greiwe JF, Pühringer T, et al. (2024). MCM double hexamer loading visualized with human proteins. Nature 636:499–508. doi.org/10.1038/s41586-024-08263-6 · doi.org/10.2210/pdb8s0c/pdb · doi.org/10.2210/pdb8s0e/pdb
• PDB 8W0F: Cryo-EM structure of a human MCM2-7 double hexamer on dsDNA. Yang R, Hunker O, Wise M, Bleichert F (2024). Multiple mechanisms for licensing human replication origins. Nature 636:488–498. doi.org/10.1038/s41586-024-08237-8 · doi.org/10.2210/pdb8w0f/pdb
• PDB 7PLO: H. sapiens replisome-CUL2/LRR1 complex. Jenkyn-Bedford M, Jones ML, Baris Y, et al. (2021). A conserved mechanism for regulating replisome disassembly in eukaryotes. Nature 600:743–747. doi.org/10.1038/s41586-021-04145-3 · doi.org/10.2210/pdb7plo/pdb
• PDB 5FTK: Cryo-EM structure of human p97 bound to ADP. Banerjee S, Bartesaghi A, Merk A, et al. (2016). 2.3 Å resolution cryo-EM structure of human p97 and mechanism of allosteric inhibition. Science 351:871–875. doi.org/10.1126/science.aad7974 · doi.org/10.2210/pdb5ftk/pdb
• PDB 1UBQ: Structure of ubiquitin refined at 1.8 Å resolution. Vijay-Kumar S, Bugg CE, Cook WJ (1987). J Mol Biol 194:531–544. doi.org/10.1016/0022-2836(87)90679-6 · doi.org/10.2210/pdb1ubq/pdb
• PDB 1KX5: X-ray structure of the nucleosome core particle, NCP147, at 1.9 Å resolution. Davey CA, Sargent DF, Luger K, Maeder AW, Richmond TJ (2002). Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 Å resolution. J Mol Biol 319:1097–1113. doi.org/10.1016/S0022-2836(02)00386-8 · doi.org/10.2210/pdb1kx5/pdb

Sequences and data

• Homo sapiens chromosome 1, GRCh38.p14 Primary Assembly, NCBI RefSeq NC_000001.11 (248,956,422 bp). www.ncbi.nlm.nih.gov/nuccore/NC_000001.11
• Arabidopsis thaliana chromosome 5, NCBI RefSeq NC_003076.8, region 3,176,876–3,181,875 (around FLC, AT5G10140); the DNA sequence drawn. www.ncbi.nlm.nih.gov/nuccore/NC_003076.8
• NASA NSSDC Planetary Fact Sheets (distances and diameters; Jupiter's minimum distance from Earth 588.5 million km; Earth equatorial radius 6,378.137 km). nssdc.gsfc.nasa.gov/planetary/factsheet/
• NASA StarChild, "The Milky Way" (diameter about 100,000 light-years). starchild.gsfc.nasa.gov/docs/StarChild/questions/question18.html