IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-63669-8.html
   My bibliography  Save this article

Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics

Author

Listed:
  • Anastasia Sosenko Piscitello

    (University of Geneva)

  • Ann-Sofie Nilsson

    (Science for Life Laboratory)

  • Michael Hawgood

    (Science for Life Laboratory)

  • Abid H. Sayyid

    (Science for Life Laboratory
    Luleå University of Technology)

  • Vasilis S. Dionellis

    (University of Geneva)

  • Giovanni Giglio

    (Science for Life Laboratory)

  • Bruno Urién

    (Science for Life Laboratory)

  • Pratikiran Bajgain

    (Science for Life Laboratory)

  • Sotirios G. Ntallis

    (University of Geneva)

  • Jiri Bartek

    (Science for Life Laboratory
    Danish Cancer Institute)

  • Thanos D. Halazonetis

    (University of Geneva)

  • Bennie Lemmens

    (Science for Life Laboratory)

Abstract

Cyclin-dependent kinases (CDKs) coordinate DNA replication and cell division, and play key roles in tissue homeostasis, genome stability and cancer development. The first step in replication is origin licensing, when minichromosome maintenance (MCM) helicases are loaded onto DNA by CDC6, CDT1 and the origin recognition complex (ORC). In yeast, origin licensing starts when CDK activity plummets in G1 phase, reinforcing the view that CDKs inhibit licensing. Here we show that, in human cells, CDK4/6 activity promotes origin licensing. By combining rapid protein degradation and time-resolved EdU-sequencing, we find that CDK4/6 activity acts epistatically to CDC6 and CDT1 in G1 phase and counteracts RB pocket proteins to promote origin licensing. Therapeutic CDK4/6 inhibitors block MCM and ORC6 loading, which we exploit to trigger mitosis with unreplicated DNA in p53-deficient cells. The CDK4/6-RB axis thus links replication licensing to proliferation, which has implications for human cell fate control and cancer therapy design.

Suggested Citation

  • Anastasia Sosenko Piscitello & Ann-Sofie Nilsson & Michael Hawgood & Abid H. Sayyid & Vasilis S. Dionellis & Giovanni Giglio & Bruno Urién & Pratikiran Bajgain & Sotirios G. Ntallis & Jiri Bartek & Th, 2025. "Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63669-8
    DOI: 10.1038/s41467-025-63669-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-63669-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-63669-8?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. Inge The & Suzan Ruijtenberg & Benjamin P. Bouchet & Alba Cristobal & Martine B. W. Prinsen & Tim van Mourik & John Koreth & Huihong Xu & Albert J. R. Heck & Anna Akhmanova & Edwin Cuppen & Mike Boxem, 2015. "Rb and FZR1/Cdh1 determine CDK4/6-cyclin D requirement in C. elegans and human cancer cells," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    2. Donglin Ding & Rongbin Zheng & Ye Tian & Rafael Jimenez & Xiaonan Hou & Saravut J. Weroha & Liguo Wang & Lei Shi & Haojie Huang, 2022. "Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Emiliano Maiani & Giacomo Milletti & Francesca Nazio & Søs Grønbæk Holdgaard & Jirina Bartkova & Salvatore Rizza & Valentina Cianfanelli & Mar Lorente & Daniele Simoneschi & Miriam Di Marco & Pasquale, 2021. "AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity," Nature, Nature, vol. 592(7856), pages 799-803, April.
    4. Jan M. Suski & Nalin Ratnayeke & Marcin Braun & Tian Zhang & Vladislav Strmiska & Wojciech Michowski & Geylani Can & Antoine Simoneau & Konrad Snioch & Mikolaj Cup & Caitlin M. Sullivan & Xiaoji Wu & , 2022. "CDC7-independent G1/S transition revealed by targeted protein degradation," Nature, Nature, vol. 605(7909), pages 357-365, May.
    5. 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.
    6. Jiaxuan Cheng & Ningning Li & Yunjing Huo & Shangyu Dang & Bik-Kwoon Tye & Ning Gao & Yuanliang Zhai, 2022. "Author Correction: Structural Insight into the MCM double hexamer activation by Dbf4-Cdc7 kinase," Nature Communications, Nature, vol. 13(1), pages 1-1, December.
    7. Aki Stubb & Sara A. Wickström, 2022. "Stretched skin cells divide without DNA replication," Nature, Nature, vol. 605(7908), pages 31-32, May.
    8. Almutasem Saleh & Yasunori Noguchi & Ricardo Aramayo & Marina E. Ivanova & Kathryn M. Stevens & Alex Montoya & S. Sunidhi & Nicolas Lopez Carranza & Marcin J. Skwark & Christian Speck, 2022. "The structural basis of Cdc7-Dbf4 kinase dependent targeting and phosphorylation of the MCM2-7 double hexamer," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    9. Jennifer N. Wells & Lucy V. Edwardes & Vera Leber & Shenaz Allyjaun & Matthew Peach & Joshua Tomkins & Antonia Kefala-Stavridi & Sarah V. Faull & Ricardo Aramayo & Carolina M. Pestana & Lepakshi Ranjh, 2025. "Reconstitution of human DNA licensing and the structural and functional analysis of key intermediates," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    10. Hana Polasek-Sedlackova & Thomas C. R. Miller & Jana Krejci & Maj-Britt Rask & Jiri Lukas, 2022. "Solving the MCM paradox by visualizing the scaffold of CMG helicase at active replisomes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    11. 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.
    12. 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.
    13. Daniele Simoneschi & Gergely Rona & Nan Zhou & Yeon-Tae Jeong & Shaowen Jiang & Giacomo Milletti & Arnaldo A. Arbini & Alfie O’Sullivan & Andrew A. Wang & Sorasicha Nithikasem & Sarah Keegan & Yik Siu, 2021. "CRL4AMBRA1 is a master regulator of D-type cyclins," Nature, Nature, vol. 592(7856), pages 789-793, April.
    14. Ran Yang & Olivia Hunker & Marleigh Wise & Franziska Bleichert, 2024. "Multiple mechanisms for licensing human replication origins," Nature, Nature, vol. 636(8042), pages 488-498, December.
    Full references (including those not matched with items on IDEAS)

    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. Shizhong Ke & Fabin Dang & Lin Wang & Jia-Yun Chen & Mandar T. Naik & Wenxue Li & Abhishek Thavamani & Nami Kim & Nandita M. Naik & Huaxiu Sui & Wei Tang & Chenxi Qiu & Kazuhiro Koikawa & Felipe Batal, 2024. "Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Jianbing Ma & Gangshun Yi & Mingda Ye & Craig MacGregor-Chatwin & Yuewen Sheng & Ying Lu & Ming Li & Qingrong Li & Dong Wang & Robert J. C. Gilbert & Peijun Zhang, 2024. "Open architecture of archaea MCM and dsDNA complexes resolved using monodispersed streptavidin affinity CryoEM," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Zhichun Xu & Jianrong Feng & Daqi Yu & Yunjing Huo & Xiaohui Ma & Wai Hei Lam & Zheng Liu & Xiang David Li & Toyotaka Ishibashi & Shangyu Dang & Yuanliang Zhai, 2023. "Synergism between CMG helicase and leading strand DNA polymerase at replication fork," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Feng Li & Hongqiang Yu & Yujun Zhang & Yuanhang Ma & Xinlei Chen & Jie Zhang & Liangbo Sun & Rui Guo & Ying Wu & Ping Zheng & Xiaojun Wang & Ping Bie & Fengtian He & Leida Zhang & Chuanming Xie & Haoj, 2025. "F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    5. Derek L. Bolhuis & Dalia Fleifel & Thomas Bonacci & Xianxi Wang & Brandon L. Mouery & Jeanette Gowen Cook & Nicholas G. Brown & Michael J. Emanuele, 2025. "USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    6. Bonnie Huang & James D. Phelan & Silvia Preite & Julio Gomez-Rodriguez & Kristoffer H. Johansen & Hirofumi Shibata & Arthur L. Shaffer & Qin Xu & Brendan Jeffrey & Martha Kirby & Stacie Anderson & Yan, 2022. "In vivo CRISPR screens reveal a HIF-1α-mTOR-network regulates T follicular helper versus Th1 cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Dylan E. Ramage & Drew W. Grant & Richard T. Timms, 2025. "Loss-of-function mutations in the dystonia gene THAP1 impair proteasome function by inhibiting PSMB5 expression," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    8. Ming Liu & Yang Wang & Fei Teng & Xinyi Mai & Xi Wang & Ming-Yuan Su & Goran Stjepanovic, 2023. "Structure of the DDB1-AMBRA1 E3 ligase receptor complex linked to cell cycle regulation," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    9. Demis Menolfi & Brian J. Lee & Hanwen Zhang & Wenxia Jiang & Nicole E. Bowen & Yunyue Wang & Junfei Zhao & Antony Holmes & Steven Gershik & Raul Rabadan & Baek Kim & Shan Zha, 2023. "ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    10. Yue Wu & Qiongdan Zhang & Yuhan Lin & Wai Hei Lam & Yuanliang Zhai, 2024. "Replication licensing regulated by a short linear motif within an intrinsically disordered region of origin recognition complex," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    11. 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.
    12. Jan Marten Schmidt & Ran Yang & Ashish Kumar & Olivia Hunker & Jan Seebacher & Franziska Bleichert, 2022. "A mechanism of origin licensing control through autoinhibition of S. cerevisiae ORC·DNA·Cdc6," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    13. 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.
    14. 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.
    15. Samah W. Awwad & Colm Doyle & Josie Coulthard & Aldo S. Bader & Nadia Gueorguieva & Simon Lam & Vipul Gupta & Rimma Belotserkovskaya & Tuan-Anh Tran & Shankar Balasubramanian & Stephen P. Jackson, 2025. "KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    16. Sarah V. Faull & Marta Barbon & Audrey Mossler & Zuanning Yuan & Lin Bai & L. Maximilian Reuter & Alberto Riera & Christian Winkler & Indiana Magdalou & Matthew Peach & Huilin Li & Christian Speck, 2025. "MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    17. 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.
    18. 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.
    19. 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.
    20. Pierre Murat & Guillaume Guilbaud & Julian E. Sale, 2024. "DNA replication initiation drives focal mutagenesis and rearrangements in human cancers," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    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:16:y:2025:i:1:d:10.1038_s41467-025-63669-8. 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.