Cited by 126DNA Repair MechanismsGenomics and Chromatin DynamicsGenomic variations and chromosomal abnormalities

Isolation and analysis of rereplicated DNA by Rerep-Seq

Open access
Menzel, Johannes, Tatman, Philip, Black, Joshua C·2020·Nucleic Acids Research

Abstract

Changes in gene copy number contribute to genomic instability, the onset and progression of cancer, developmental abnormalities and adaptive potential. The origins of gene amplifications have remained elusive; however, DNA rereplication has been implicated as a source of gene amplifications. The inability to determine which sequences are rereplicated and under what conditions have made it difficult to determine the validity of the proposed models. Here we present Rerep-Seq, a technique that selectively enriches for rereplicated DNA in preparation for analysis by DNA sequencing that can be applied to any species. We validated Rerep-Seq by simulating DNA rereplication in yeast and human cells. Using Rerep-Seq, we demonstrate that rereplication induced in Saccharomyces cerevisiae by deregulated origin licensing is non-random and defined by broad domains that span multiple replication origins and topological boundaries.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/nar/gkaa197

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • We filtered intragenic CAGE TCs with GG-initiation and those overlapping with coding exons and annotated enhancers.

    “We filtered intragenic CAGE TCs with GG-initiation and those overlapping with coding exons and annotated enhancers24,70”

    From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [70]

    The Materials and Methods sections describe filtering Rerep-Seq data and analyzing replication-timing regions, not intragenic CAGE transcription clusters. Searches for GG-initiation, CAGE clusters, coding exons, and enhancer filtering found no passage addressing the cited claim; page numbers are unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

No references could be resolved yet.

Research works printed but not linked: 38

  1. [1]Bleichert F., Botchan M.R., Berger J.M. Mechanisms for initiating cellular DNA replication. Science (80-.). 2017; 355: eaah6317. 28209641
  2. [2]Fragkos M., Ganier O., Coulombe P., Méchali M. DNA replication origin activation in space and time. Nat. Rev. Mol. Cell Biol. 2015; 16: 360– 374. 25999062
  3. [3]Reams A.B., Roth J.R. Mechanisms of gene duplication and amplification. Cold Spring Harb. Perspect. Biol. 2015; 7: a016592– a016592. 25646380 PMC4315931
  4. [4]Zhang F., Gu W., Hurles M.E., Lupski J.R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 2009; 10: 451– 481. 19715442 PMC4472309
  5. [5]Milhollen M.A., Narayanan U., Soucy T.A., Veiby P.O., Smith P.G., Amidon B. Inhibition of NEDD8-activating enzyme induces rereplication and apoptosis in human tumor cells consistent with deregulating CDT1 turnover. Cancer Res. 2011; 71: 3042– 3051. 21487042
  6. [6]Klotz-Noack K., McIntosh D., Schurch N., Pratt N., Blow J.J. Re-replication induced by geminin depletion occurs from G2 and is enhanced by checkpoint activation. J. Cell Sci. 2012; 125: 2436– 2445. 22366459 PMC3481538
  7. [7]Soucy T.A., Smith P.G., Milhollen M.A., Berger A.J., Gavin J.M., Adhikari S., Brownell J.E., Burke K.E., Cardin D.P., Critchley S. et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009; 458: 732– 736. 19360080
  8. [8]Muñoz S., Búa S., Rodríguez-Acebes S., Megías D., Ortega S., de Martino A., Méndez J. In Vivo DNA Re-replication elicits lethal tissue dysplasias. Cell Rep. 2017; 19: 928– 938. 28467906
  9. [9]Davidson I.F., Li A., Blow J.J. Deregulated replication licensing causes DNA fragmentation consistent with head-to-tail fork collision. Mol. Cell. 2006; 24: 433– 443. 17081992 PMC1819398
  10. [10]Neelsen K.J., Zanini I.M.Y., Mijic S., Herrador R., Zellweger R., Ray Chaudhuri A., Creavin K.D., Blow J.J., Lopes M. Deregulated origin licensing leads to chromosomal breaks by rereplication of a gapped DNA template. Genes Dev. 2013; 27: 2537– 2542. 24298053 PMC3861667
  11. [11]Green B.M., Finn K.J., Li J.J. Loss of DNA replication control is a potent inducer of gene amplification. Science (80-.). 2010; 329: 943– 946. PMC3700424 20724634
  12. [12]Blow J.J., Gillespie P.J. Replication licensing and cancer - a fatal entanglement. Nat. Rev. Cancer. 2008; 8: 799– 806. 18756287 PMC2577763
  13. [13]Liontos M., Koutsami M., Sideridou M., Evangelou K., Kletsas D., Levy B., Kotsinas A., Nahum O., Zoumpourlis V., Kouloukoussa M. et al. Deregulated overexpression of hCdt1 and hCdc6 promotes malignant behavior. Cancer Res. 2007; 67: 10899– 10909. 18006835
  14. [14]Zhong Y., Nellimootti T., Peace J.M., Knott S.R. V, Villwock S.K., Yee J.M., Jancuska J.M., Rege S., Tecklenburg M., Sclafani R.A. et al. The level of origin firing inversely affects the rate of replication fork progression. J. Cell Biol. 2013; 201: 373– 383. 23629964 PMC3639389
  15. [15]Viggiani C.J., Aparicio O.M. New vectors for simplified construction of BrdU-Incorporating strains of Saccharomyces cerevisiae. Yeast. 2006; 23: 1045– 1051. 17083135
  16. [16]Liu F., Ren C., Li H., Zhou P., Bo X., Shu W. De novo identification of replication-timing domains in the human genome by deep learning. Bioinformatics. 2016; 32: 641– 649. 26545821 PMC4795613
  17. [17]Siow C.C., Nieduszynska S.R., Müller C.A., Nieduszynski C.A. OriDB, the DNA replication origin database updated and extended. Nucleic Acids Res. 2011; 40: D682– D686. 22121216 PMC3245157
  18. [18]Raghuraman M.K., Winzeler E.A., Collingwood D., Hunt S., Wodicka L., Conway A., Lockhart D.J., Davis R.W., Brewer B.J., Fangman W.L. Replication dynamics of the yeast genome. Science (80-.). 2001; 294: 115– 121. 11588253
  19. [19]Adey A., Shendure J. Ultra-low-input, tagmentation-based whole-genome bisulfite sequencing. Genome Res. 2012; 22: 1139– 1143. 22466172 PMC3371708
  20. [20]Magnusson J., Orth M., Lestienne P., Taanman J. -W. Replication of mitochondrial DNA occurs throughout the mitochondria of cultured human cells. Exp. Cell Res. 2003; 289: 133– 142. 12941611
  21. [21]Williamson D.H., Moustacchi E. The synthesis of mitochondrial DNA during the cell cycle in the yeast Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 1971; 42: 195– 201. 5545511
  22. [22]Müller C.A., Hawkins M., Retkute R., Malla S., Wilson R., Blythe M.J., Nakato R., Komata M., Shirahige K., de Moura A.P.S. et al. The dynamics of genome replication using deep sequencing. Nucleic Acids Res. 2014; 42: e3. 24089142 PMC3874191
  23. [23]Müller C.A., Nieduszynski C.A. Conservation of replication timing reveals global and local regulation of replication origin activity. Genome Res. 2012; 22: 1953– 1962. 22767388 PMC3460190
  24. [24]Marchal C., Sima J., Gilbert D.M. Control of DNA replication timing in the 3D genome. Nat. Rev. Mol. Cell Biol. 2019; 20: 721– 737. 31477886 PMC11567694
  25. [25]Yaffe E., Farkash-Amar S., Polten A., Yakhini Z., Tanay A., Simon I. Comparative analysis of DNA replication timing reveals conserved large-scale chromosomal architecture. PLoS Genet. 2010; 6: e1001011. 20617169 PMC2895651
  26. [26]Hansen R.S., Thomas S., Sandstrom R., Canfield T.K., Thurman R.E., Weaver M., Dorschner M.O., Gartler S.M., Stamatoyannopoulos J.A. Sequencing newly replicated DNA reveals widespread plasticity in human replication timing. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 139– 144. 19966280 PMC2806781
  27. [27]Truong L.N., Wu X. Prevention of DNA re-replication in eukaryotic cells. J. Mol. Cell Biol. 2011; 3: 13– 22. 21278447 PMC3030972
  28. [28]Tanaka S., Araki H. Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance. PLoS Genet. 2011; 7: e1002136. 21698130 PMC3116906
  29. [29]Calvi B.R., Lilly M.A., Spradling A.C. Cell cycle control of chorion gene amplification. Genes Dev. 1998; 12: 734– 744. 9499407 PMC316579
  30. [30]Klotz-Noack K., McIntosh D., Schurch N., Pratt N., Blow J.J. Re-replication induced by geminin depletion occurs from G2 and is enhanced by checkpoint activation. J. Cell Sci. 2012; 125: 2436– 44425. 22366459 PMC3481538
  31. [31]Tanaka S., Umemori T., Hirai K., Muramatsu S., Kamimura Y., Araki H. CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast. Nature. 2007; 445: 328– 332. 17167415
  32. [32]Eser U., Chandler-Brown D., Ay F., Straight A.F., Duan Z., Noble W.S., Skotheim J.M. Form and function of topologically associating genomic domains in budding yeast. Proc. Natl. Acad. Sci. U.S.A. 2017; 114: E3061– E3070. 28348222 PMC5393236
  33. [33]Slager J., Kjos M., Attaiech L., Veening J.W. Antibiotic-induced replication stress triggers bacterial competence by increasing gene dosage near the origin. Cell. 2014; 157: 395– 406. 24725406
  34. [34]Black J.C., Atabakhsh E., Kim J., Biette K.M., Van Rechem C., Ladd B., Burrowes P.D., Donado C., Mattoo H., Kleinstiver B.P. et al. Hypoxia drives transient site-specific copy gain and drug-resistant gene expression. Genes Dev. 2015; 29: 1018– 1031. 25995187 PMC4441050
  35. [35]Petrakis T.G., Komseli E. -S., Papaioannou M., Vougas K., Polyzos A., Myrianthopoulos V., Mikros E., Trougakos I.P., Thanos D., Branzei D. et al. Exploring and exploiting the systemic effects of deregulated replication licensing. Semin. Cancer Biol. 2016; 37–38: 3– 15. 26707000
  36. [36]Karakaidos P., Taraviras S., Vassiliou L.V., Zacharatos P., Kastrinakis N.G., Kougiou D., Kouloukoussa M., Nishitani H., Papavassiliou A.G., Lygerou Z. et al. Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas. Am. J. Pathol. 2004; 165: 1351– 1365. 15466399 PMC1618634
  37. [37]Hastings P.J., Lupski J.R., Rosenberg S.M., Ira G. Mechanisms of change in gene copy number. Nat. Rev. Genet. 2009; 10: 551– 564. 19597530 PMC2864001
  38. [38]Schimke R.T., Sherwood S.W., Hill A.B., Johnstont R.N. Overreplication and recombination of DNA in higher eukaryotes: Potential consequences and biological implications. Genetics. 1986; 83: 2157– 2161. PMC323250 3457380

Authors
Menzel, J., Tatman, P., & Black, J. C.
Affiliations
University of Colorado Anschutz (US)
Corresponding author
Black, Joshua C
Venue
Nucleic Acids Research
Published
2020-04-02
Volume
48
Issue
10
Pages
e58-e58
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
OpenAlex
W3014366315
Cited by
126
References
0
Citations by year
2026: 17 · 2025: 27 · 2024: 22 · 2023: 23 · 2022: 23 · 2021: 12 · 2020: 2
FWCI
4.87
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institute of General Medical Sciences (1R35GM128720-01)
  • Boettcher Foundation (25A6182)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
DNA re-replication, gene amplification, genomic instability, origin of replication, origin licensing, Saccharomyces cerevisiae, topological domains, copy number variation
MeSH terms
Cell Line, DNA Replication, Humans, Saccharomyces cerevisiae, Sequence Analysis, DNA

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review