IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34379-2.html
   My bibliography  Save this article

Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions

Author

Listed:
  • Karl-Uwe Reusswig

    (Max Planck Institute of Biochemistry
    Blavatnik Institute, Harvard Medical School
    Dana-Farber Cancer Institute)

  • Julia Bittmann

    (Max Planck Institute of Biochemistry)

  • Martina Peritore

    (Max Planck Institute of Biochemistry
    Institute of Aerospace Medicine, German Aerospace Center (DLR))

  • Mathilde Courtes

    (Université de Montpellier – Centre National de la Recherche Scientifique)

  • Benjamin Pardo

    (Université de Montpellier – Centre National de la Recherche Scientifique)

  • Michael Wierer

    (Max Planck Institute of Biochemistry
    University of Copenhagen)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

  • Boris Pfander

    (Max Planck Institute of Biochemistry
    Institute of Aerospace Medicine, German Aerospace Center (DLR)
    CECAD Research Center, University of Cologne)

Abstract

DNA replicates once per cell cycle. Interfering with the regulation of DNA replication initiation generates genome instability through over-replication and has been linked to early stages of cancer development. Here, we engineer genetic systems in budding yeast to induce unscheduled replication in a G1-like cell cycle state. Unscheduled G1 replication initiates at canonical S-phase origins. We quantifiy the composition of replisomes in G1- and S-phase and identified firing factors, polymerase α, and histone supply as factors that limit replication outside S-phase. G1 replication per se does not trigger cellular checkpoints. Subsequent replication during S-phase, however, results in over-replication and leads to chromosome breaks and chromosome-wide, strand-biased occurrence of RPA-bound single-stranded DNA, indicating head-to-tail replication collisions as a key mechanism generating genome instability upon G1 replication. Low-level, sporadic induction of G1 replication induces an identical response, indicating findings from synthetic systems are applicable to naturally occurring scenarios of unscheduled replication initiation.

Suggested Citation

  • Karl-Uwe Reusswig & Julia Bittmann & Martina Peritore & Mathilde Courtes & Benjamin Pardo & Michael Wierer & Matthias Mann & Boris Pfander, 2022. "Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34379-2
    DOI: 10.1038/s41467-022-34379-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34379-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34379-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Philip Zegerman & John F. X. Diffley, 2007. "Phosphorylation of Sld2 and Sld3 by cyclin-dependent kinases promotes DNA replication in budding yeast," Nature, Nature, vol. 445(7125), pages 281-285, January.
    2. Haiqing Fu & Christophe E. Redon & Bhushan L. Thakur & Koichi Utani & Robin Sebastian & Sang-Min Jang & Jacob M. Gross & Sara Mosavarpour & Anna B. Marks & Sophie Z. Zhuang & Sarah B. Lazar & Mishal R, 2021. "Dynamics of replication origin over-activation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Seiji Tanaka & Toshiko Umemori & Kazuyuki Hirai & Sachiko Muramatsu & Yoichiro Kamimura & Hiroyuki Araki, 2007. "CDK-dependent phosphorylation of Sld2 and Sld3 initiates DNA replication in budding yeast," Nature, Nature, vol. 445(7125), pages 328-332, January.
    4. Sang-Min Jang & Ya Zhang & Koichi Utani & Haiqing Fu & Christophe E. Redon & Anna B. Marks & Owen K. Smith & Catherine J. Redmond & Adrian M. Baris & Danielle A. Tulchinsky & Mirit I. Aladjem, 2018. "The replication initiation determinant protein (RepID) modulates replication by recruiting CUL4 to chromatin," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    5. Van Q. Nguyen & Carl Co & Joachim J. Li, 2001. "Cyclin-dependent kinases prevent DNA re-replication through multiple mechanisms," Nature, Nature, vol. 411(6841), pages 1068-1073, June.
    6. Benaglia, Tatiana & Chauveau, Didier & Hunter, David R. & Young, Derek S., 2009. "mixtools: An R Package for Analyzing Mixture Models," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 32(i06).
    7. Jaime Lopez-Mosqueda & Nancy L. Maas & Zophonias O. Jonsson & Lisa G. DeFazio-Eli & James Wohlschlegel & David P. Toczyski, 2010. "Damage-induced phosphorylation of Sld3 is important to block late origin firing," Nature, Nature, vol. 467(7314), pages 479-483, September.
    8. Susanne C. S. Bantele & Michael Lisby & Boris Pfander, 2019. "Quantitative sensing and signalling of single-stranded DNA during the DNA damage response," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    9. Jirina Bartkova & Nousin Rezaei & Michalis Liontos & Panagiotis Karakaidos & Dimitris Kletsas & Natalia Issaeva & Leandros-Vassilios F. Vassiliou & Evangelos Kolettas & Katerina Niforou & Vassilis C. , 2006. "Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints," Nature, Nature, vol. 444(7119), pages 633-637, November.
    10. Morgane Macheret & Thanos D. Halazonetis, 2018. "Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress," Nature, Nature, vol. 555(7694), pages 112-116, March.
    11. Katsuhiko Shirahige & Yuji Hori & Katsuya Shiraishi & Minoru Yamashita & Keiko Takahashi & Chikashi Obuse & Toshiki Tsurimoto & Hiroshi Yoshikawa, 1998. "Regulation of DNA-replication origins during cell-cycle progression," Nature, Nature, vol. 395(6702), pages 618-621, October.
    12. Yi-Jun Sheu & Bruce Stillman, 2010. "The Dbf4–Cdc7 kinase promotes S phase by alleviating an inhibitory activity in Mcm4," Nature, Nature, vol. 463(7277), pages 113-117, January.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Lorenzo Galanti & Martina Peritore & Robert Gnügge & Elda Cannavo & Johannes Heipke & Maria Dilia Palumbieri & Barbara Steigenberger & Lorraine S. Symington & Petr Cejka & Boris Pfander, 2024. "Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Arianna Penzo & Marion Dubarry & Clémentine Brocas & Myriam Zheng & Raphaël M. Mangione & Mathieu Rougemaille & Coralie Goncalves & Ophélie Lautier & Domenico Libri & Marie-Noëlle Simon & Vincent Géli, 2023. "A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Aftab Amin & Cheung Man Hei & Chun Liang & Aftab Amin & Cheung Man Hei & Chun Liang & Chun Liang & Aftab Amin & Cheung Man Hei & Chun Liang, 2019. "DNA Replication-Initiation Proteins in Eukaryotic Cells," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 22(5), pages 17042-17049, December.
    2. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Juan Manuel Valverde & Geronimo Dubra & Michael Phillips & Austin Haider & Carlos Elena-Real & Aurélie Fournet & Emile Alghoul & Dhanvantri Chahar & Nuria Andrés-Sanchez & Matteo Paloni & Pau Bernadó , 2023. "A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Matthew Day & Bilal Tetik & Milena Parlak & Yasser Almeida-Hernández & Markus Räschle & Farnusch Kaschani & Heike Siegert & Anika Marko & Elsa Sanchez-Garcia & Markus Kaiser & Isabel A. Barker & Laure, 2024. "TopBP1 utilises a bipartite GINS binding mode to support genome replication," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    5. Lorenzo Galanti & Martina Peritore & Robert Gnügge & Elda Cannavo & Johannes Heipke & Maria Dilia Palumbieri & Barbara Steigenberger & Lorraine S. Symington & Petr Cejka & Boris Pfander, 2024. "Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    6. Jiaxuan Cheng & Ningning Li & Yunjing Huo & Shangyu Dang & Bik-Kwoon Tye & Ning Gao & Yuanliang Zhai, 2022. "Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Anna C. Papageorgiou & Michaela Pospisilova & Jakub Cibulka & Raghib Ashraf & Christopher A. Waudby & Pavel Kadeřávek & Volha Maroz & Karel Kubicek & Zbynek Prokop & Lumir Krejci & Konstantinos Tripsi, 2023. "Recognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    8. Ozonder, Gozde & Miller, Eric J., 2021. "Longitudinal investigation of skeletal activity episode timing decisions – A copula approach," Journal of choice modelling, Elsevier, vol. 40(C).
    9. Elias Einig & Chao Jin & Valentina Andrioletti & Boris Macek & Nikita Popov, 2023. "RNAPII-dependent ATM signaling at collisions with replication forks," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Minjung Kyung & Ju-Hyun Park & Ji Yeh Choi, 2022. "Bayesian Mixture Model of Extended Redundancy Analysis," Psychometrika, Springer;The Psychometric Society, vol. 87(3), pages 946-966, September.
    11. Anneke Brümmer & Carlos Salazar & Vittoria Zinzalla & Lilia Alberghina & Thomas Höfer, 2010. "Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication," PLOS Computational Biology, Public Library of Science, vol. 6(5), pages 1-13, May.
    12. Xue, Jiacheng & Yao, Weixin, 2022. "Machine Learning Embedded Semiparametric Mixtures of Regressions with Covariate-Varying Mixing Proportions," Econometrics and Statistics, Elsevier, vol. 22(C), pages 159-171.
    13. Samuel Hume & Claudia P. Grou & Pauline Lascaux & Vincenzo D’Angiolella & Arnaud J. Legrand & Kristijan Ramadan & Grigory L. Dianov, 2021. "The NUCKS1-SKP2-p21/p27 axis controls S phase entry," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    14. Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    15. Derek S. Young & Xi Chen & Dilrukshi C. Hewage & Ricardo Nilo-Poyanco, 2019. "Finite mixture-of-gamma distributions: estimation, inference, and model-based clustering," Advances in Data Analysis and Classification, Springer;German Classification Society - Gesellschaft für Klassifikation (GfKl);Japanese Classification Society (JCS);Classification and Data Analysis Group of the Italian Statistical Society (CLADAG);International Federation of Classification Societies (IFCS), vol. 13(4), pages 1053-1082, December.
    16. Zihao Wang & Wenxi Wang & Xiaoming Xie & Yongfa Wang & Zhengzhao Yang & Huiru Peng & Mingming Xin & Yingyin Yao & Zhaorong Hu & Jie Liu & Zhenqi Su & Chaojie Xie & Baoyun Li & Zhongfu Ni & Qixin Sun &, 2022. "Dispersed emergence and protracted domestication of polyploid wheat uncovered by mosaic ancestral haploblock inference," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Dalla Valle, Luciana & De Giuli, Maria Elena & Tarantola, Claudia & Manelli, Claudio, 2016. "Default probability estimation via pair copula constructions," European Journal of Operational Research, Elsevier, vol. 249(1), pages 298-311.
    18. Zhang, Liyuan & Zhang, Huihui & Han, Wenting & Niu, Yaxiao & Chávez, José L. & Ma, Weitong, 2021. "The mean value of gaussian distribution of excess green index: A new crop water stress indicator," Agricultural Water Management, Elsevier, vol. 251(C).
    19. Sascha Schäuble & Karolin Klement & Shiva Marthandan & Sandra Münch & Ines Heiland & Stefan Schuster & Peter Hemmerich & Stephan Diekmann, 2012. "Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-14, August.
    20. Ivana Malá, 2013. "Použití konečných směsí logaritmicko-normálních rozdělení pro modelování příjmů českých domácností [The Use of Finite Mixtures of Lognormal Distribution for the Modelling of Household Income Distri," Politická ekonomie, Prague University of Economics and Business, vol. 2013(3), pages 356-372.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34379-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.