IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46824-5.html
   My bibliography  Save this article

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

Author

Listed:
  • Ke Cong

    (University of Massachusetts Chan Medical School)

  • Nathan MacGilvary

    (University of Massachusetts Chan Medical School)

  • Silviana Lee

    (University of Massachusetts Chan Medical School)

  • Shannon G. MacLeod

    (Northeastern University Biology Department 360 Huntington Avenue)

  • Jennifer Calvo

    (University of Massachusetts Chan Medical School)

  • Min Peng

    (University of Massachusetts Chan Medical School)

  • Arne Nedergaard Kousholt

    (Oncode Institute, The Netherlands Cancer Institute)

  • Tovah A. Day

    (Northeastern University Biology Department 360 Huntington Avenue)

  • Sharon B. Cantor

    (University of Massachusetts Chan Medical School)

Abstract

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in creating single-stranded DNA gaps and inducing sensitivity requires the FANCJ DNA helicase. Yet, how FANCJ relates to PARP1 inhibition or trapping, which contribute to PARPi toxicity, remains unclear. Here, we find PARPi effectiveness hinges on S-phase PARP1 activity, which is reduced in FANCJ deficient cells as G-quadruplexes sequester PARP1 and MSH2. Additionally, loss of the FANCJ-MLH1 interaction diminishes PARP1 activity; however, depleting MSH2 reinstates PARPi sensitivity and gaps. Indicating sequestered and trapped PARP1 are distinct, FANCJ loss increases PARPi resistance in cells susceptible to PARP1 trapping. However, with BRCA1 deficiency, the loss of FANCJ mirrors PARP1 loss or inhibition, with the detrimental commonality being loss of S-phase PARP1 activity. These insights underline the crucial role of PARP1 activity during DNA replication in BRCA1 deficient cells and emphasize the importance of understanding drug mechanisms for enhancing therapeutic response.

Suggested Citation

  • Ke Cong & Nathan MacGilvary & Silviana Lee & Shannon G. MacLeod & Jennifer Calvo & Min Peng & Arne Nedergaard Kousholt & Tovah A. Day & Sharon B. Cantor, 2024. "FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46824-5
    DOI: 10.1038/s41467-024-46824-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46824-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46824-5?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. Apolinar Maya-Mendoza & Pavel Moudry & Joanna Maria Merchut-Maya & MyungHee Lee & Robert Strauss & Jiri Bartek, 2018. "High speed of fork progression induces DNA replication stress and genomic instability," Nature, Nature, vol. 559(7713), pages 279-284, July.
    2. Fiona M. Behan & Francesco Iorio & Gabriele Picco & Emanuel Gonçalves & Charlotte M. Beaver & Giorgia Migliardi & Rita Santos & Yanhua Rao & Francesco Sassi & Marika Pinnelli & Rizwan Ansari & Sarah H, 2019. "Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens," Nature, Nature, vol. 568(7753), pages 511-516, April.
    3. Jone Michelena & Aleksandra Lezaja & Federico Teloni & Thomas Schmid & Ralph Imhof & Matthias Altmeyer, 2018. "Analysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    4. Stephen J. Pettitt & Dragomir B. Krastev & Inger Brandsma & Amy Dréan & Feifei Song & Radoslav Aleksandrov & Maria I. Harrell & Malini Menon & Rachel Brough & James Campbell & Jessica Frankum & Michae, 2018. "Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    5. Johannes Rudolph & Genevieve Roberts & Karolin Luger, 2021. "Histone Parylation factor 1 contributes to the inhibition of PARP1 by cancer drugs," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    6. Sylvie M. Noordermeer & Salomé Adam & Dheva Setiaputra & Marco Barazas & Stephen J. Pettitt & Alexanda K. Ling & Michele Olivieri & Alejandro Álvarez-Quilón & Nathalie Moatti & Michal Zimmermann & Ste, 2018. "The shieldin complex mediates 53BP1-dependent DNA repair," Nature, Nature, vol. 560(7716), pages 117-121, August.
    7. Hannah Farmer & Nuala McCabe & Christopher J. Lord & Andrew N. J. Tutt & Damian A. Johnson & Tobias B. Richardson & Manuela Santarosa & Krystyna J. Dillon & Ian Hickson & Charlotte Knights & Niall M. , 2005. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy," Nature, Nature, vol. 434(7035), pages 917-921, April.
    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. Diego Dibitetto & Martin Liptay & Francesca Vivalda & Hülya Dogan & Ewa Gogola & Martín González Fernández & Alexandra Duarte & Jonas A. Schmid & Morgane Decollogny & Paola Francica & Sara Przetocka &, 2024. "H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Arindam Datta & Kajal Biswas & Joshua A. Sommers & Haley Thompson & Sanket Awate & Claudia M. Nicolae & Tanay Thakar & George-Lucian Moldovan & Robert H. Shoemaker & Shyam K. Sharan & Robert M. Brosh, 2021. "WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    3. Sumin Feng & Sai Ma & Kejiao Li & Shengxian Gao & Shaokai Ning & Jinfeng Shang & Ruiyuan Guo & Yingying Chen & Britny Blumenfeld & Itamar Simon & Qing Li & Rong Guo & Dongyi Xu, 2022. "RIF1-ASF1-mediated high-order chromatin structure safeguards genome integrity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Domagoj Vugic & Isaac Dumoulin & Charlotte Martin & Anna Minello & Lucia Alvaro-Aranda & Jesus Gomez-Escudero & Rady Chaaban & Rana Lebdy & Catharina Nicolai & Virginie Boucherit & Cyril Ribeyre & Ang, 2023. "Replication gap suppression depends on the double-strand DNA binding activity of BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Anne Margriet Heijink & Colin Stok & David Porubsky & Eleni Maria Manolika & Jurrian K. Kanter & Yannick P. Kok & Marieke Everts & H. Rudolf Boer & Anastasia Audrey & Femke J. Bakker & Elles Wierenga , 2022. "Sister chromatid exchanges induced by perturbed replication can form independently of BRCA1, BRCA2 and RAD51," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Zuzana Machacova & Katarina Chroma & David Lukac & Iva Protivankova & Pavel Moudry, 2024. "DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    7. Megan E. Luedeman & Susanna Stroik & Wanjuan Feng & Adam J. Luthman & Gaorav P. Gupta & Dale A. Ramsden, 2022. "Poly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Takuya Tsujino & Tomoaki Takai & Kunihiko Hinohara & Fu Gui & Takeshi Tsutsumi & Xiao Bai & Chenkui Miao & Chao Feng & Bin Gui & Zsofia Sztupinszki & Antoine Simoneau & Ning Xie & Ladan Fazli & Xuesen, 2023. "CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    9. Yajie Sun & Jeffrey Patterson-Fortin & Sen Han & Zhe Li & Zuzanna Nowicka & Yuna Hirohashi & Susan Kilgas & Jae Kyo Yi & Alexander Spektor & Wojciech Fendler & Panagiotis A. Konstantinopoulos & Dipanj, 2024. "53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    10. Neil J. Rzechorzek & Simone Kunzelmann & Andrew G. Purkiss & Mariana Silva Dos Santos & James I. MacRae & Ian A. Taylor & Kasper Fugger & Stephen C. West, 2023. "Mechanism of substrate hydrolysis by the human nucleotide pool sanitiser DNPH1," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    11. Alexendar R. Perez & Laura Sala & Richard K. Perez & Joana A. Vidigal, 2021. "CSC software corrects off-target mediated gRNA depletion in CRISPR-Cas9 essentiality screens," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    12. Xuefeng Wang & Shuo Zhang & Yuqin liu, 2022. "ITGInsight–discovering and visualizing research fronts in the scientific literature," Scientometrics, Springer;Akadémiai Kiadó, vol. 127(11), pages 6509-6531, November.
    13. Vanessa Rousseau & Elias Einig & Chao Jin & Julia Horn & Mathias Riebold & Tanja Poth & Mohamed-Ali Jarboui & Michael Flentje & Nikita Popov, 2023. "Trim33 masks a non-transcriptional function of E2f4 in replication fork progression," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    14. Heathcliff Dorado García & Fabian Pusch & Yi Bei & Jennifer Stebut & Glorymar Ibáñez & Kristina Guillan & Koshi Imami & Dennis Gürgen & Jana Rolff & Konstantin Helmsauer & Stephanie Meyer-Liesener & N, 2022. "Therapeutic targeting of ATR in alveolar rhabdomyosarcoma," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    15. Sundarraj Jayakumar & Manthan Patel & Fanny Boulet & Hadicha Aziz & Greg N. Brooke & Hemanth Tummala & Madapura M. Pradeepa, 2024. "PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    16. Zizhi Tang & Ming Zeng & Xiaojun Wang & Chang Guo & Peng Yue & Xiaohu Zhang & Huiqiang Lou & Jun Chen & Dezhi Mu & Daochun Kong & Antony M. Carr & Cong Liu, 2022. "Synthetic lethality between TP53 and ENDOD1," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    17. Samuel D. Chauvin & Shoichiro Ando & Joe A. Holley & Atsushi Sugie & Fang R. Zhao & Subhajit Poddar & Rei Kato & Cathrine A. Miner & Yohei Nitta & Siddharth R. Krishnamurthy & Rie Saito & Yue Ning & Y, 2024. "Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    18. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    19. Meng Wang & Satoshi Fukushima & Yi-Shuan Sheen & Egle Ramelyte & Noel Cruz-Pacheco & Chenxu Shi & Shanshan Liu & Ishani Banik & Jamie D. Aquino & Martin Sangueza Acosta & Mitchell Levesque & Reinhard , 2024. "The genetic evolution of acral melanoma," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    20. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," 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:15:y:2024:i:1:d:10.1038_s41467-024-46824-5. 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.