IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46283-y.html
   My bibliography  Save this article

GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer

Author

Listed:
  • Zu Ye

    (The University of Texas MD Anderson Cancer Center
    Chinese Academy of Sciences)

  • Shengfeng Xu

    (The University of Texas MD Anderson Cancer Center)

  • Yin Shi

    (Zhejiang University School of Medicine
    The University of Texas MD Anderson Cancer Center)

  • Xueqian Cheng

    (The University of Texas MD Anderson Cancer Center)

  • Yuan Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Sunetra Roy

    (University of Texas MD Anderson Cancer Center)

  • Sarita Namjoshi

    (The University of Texas MD Anderson Cancer Center)

  • Michael A. Longo

    (The University of Texas MD Anderson Cancer Center)

  • Todd M. Link

    (The University of Texas MD Anderson Cancer Center)

  • Katharina Schlacher

    (University of Texas MD Anderson Cancer Center)

  • Guang Peng

    (The University of Texas MD Anderson Cancer Center)

  • Dihua Yu

    (The University of Texas MD Anderson Cancer Center)

  • Bin Wang

    (The University of Texas MD Anderson Cancer Center)

  • John A. Tainer

    (The University of Texas MD Anderson Cancer Center)

  • Zamal Ahmed

    (The University of Texas MD Anderson Cancer Center)

Abstract

Growth factor receptor-bound protein 2 (GRB2) is a cytoplasmic adapter for tyrosine kinase signaling and a nuclear adapter for homology-directed-DNA repair. Here we find nuclear GRB2 protects DNA at stalled replication forks from MRE11-mediated degradation in the BRCA2 replication fork protection axis. Mechanistically, GRB2 binds and inhibits RAD51 ATPase activity to stabilize RAD51 on stalled replication forks. In GRB2-depleted cells, PARP inhibitor (PARPi) treatment releases DNA fragments from stalled forks into the cytoplasm that activate the cGAS–STING pathway to trigger pro-inflammatory cytokine production. Moreover in a syngeneic mouse metastatic ovarian cancer model, GRB2 depletion in the context of PARPi treatment reduced tumor burden and enabled high survival consistent with immune suppression of cancer growth. Collective findings unveil GRB2 function and mechanism for fork protection in the BRCA2-RAD51-MRE11 axis and suggest GRB2 as a potential therapeutic target and an enabling predictive biomarker for patient selection for PARPi and immunotherapy combination.

Suggested Citation

  • Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46283-y
    DOI: 10.1038/s41467-024-46283-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46283-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46283-y?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. Sofija Mijic & Ralph Zellweger & Nagaraja Chappidi & Matteo Berti & Kurt Jacobs & Karun Mutreja & Sebastian Ursich & Arnab Ray Chaudhuri & Andre Nussenzweig & Pavel Janscak & Massimo Lopes, 2017. "Replication fork reversal triggers fork degradation in BRCA2-defective cells," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Arnab Ray Chaudhuri & Elsa Callen & Xia Ding & Ewa Gogola & Alexandra A. Duarte & Ji-Eun Lee & Nancy Wong & Vanessa Lafarga & Jennifer A. Calvo & Nicholas J. Panzarino & Sam John & Amanda Day & Anna V, 2016. "Replication fork stability confers chemoresistance in BRCA-deficient cells," Nature, Nature, vol. 535(7612), pages 382-387, July.
    3. Julie L. Tubbs & Vitaly Latypov & Sreenivas Kanugula & Amna Butt & Manana Melikishvili & Rolf Kraehenbuehl & Oliver Fleck & Andrew Marriott & Amanda J. Watson & Barbara Verbeek & Gail McGown & Mary Th, 2009. "Flipping of alkylated DNA damage bridges base and nucleotide excision repair," Nature, Nature, vol. 459(7248), pages 808-813, June.
    4. Flavie Coquel & Maria-Joao Silva & Hervé Técher & Karina Zadorozhny & Sushma Sharma & Jadwiga Nieminuszczy & Clément Mettling & Elodie Dardillac & Antoine Barthe & Anne-Lyne Schmitz & Alexy Promonet &, 2018. "SAMHD1 acts at stalled replication forks to prevent interferon induction," Nature, Nature, vol. 557(7703), pages 57-61, May.
    5. Michael A. Longo & Sunetra Roy & Yue Chen & Karl-Heinz Tomaszowski & Andrew S. Arvai & Jordan T. Pepper & Rebecca A. Boisvert & Selvi Kunnimalaiyaan & Caezanne Keshvani & David Schild & Albino Bacolla, 2023. "RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Zamal Ahmed & Zahra Timsah & Kin M. Suen & Nathan P. Cook & Gilbert R. Lee & Chi-Chuan Lin & Mihai Gagea & Angel A. Marti & John E. Ladbury, 2015. "Grb2 monomer–dimer equilibrium determines normal versus oncogenic function," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    7. Timo Reisländer & Emilia Puig Lombardi & Florian J. Groelly & Ana Miar & Manuela Porru & Serena Vito & Benjamin Wright & Helen Lockstone & Annamaria Biroccio & Adrian Harris & Arturo Londoño-Vallejo &, 2019. "BRCA2 abrogation triggers innate immune responses potentiated by treatment with PARP inhibitors," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    8. Gregory M. Findlay & Riza M. Daza & Beth Martin & Melissa D. Zhang & Anh P. Leith & Molly Gasperini & Joseph D. Janizek & Xingfan Huang & Lea M. Starita & Jay Shendure, 2018. "Accurate classification of BRCA1 variants with saturation genome editing," Nature, Nature, vol. 562(7726), pages 217-222, October.
    9. Zamal Ahmed & Zahra Timsah & Kin M. Suen & Nathan P. Cook & Gilbert R. Lee IV & Chi-Chuan Lin & Mihai Gagea & Angel A. Marti & John E. Ladbury, 2015. "Correction: Corrigendum: Grb2 monomer–dimer equilibrium determines normal versus oncogenic function," Nature Communications, Nature, vol. 6(1), pages 1-2, November.
    10. 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.
    11. Arnab Ray Chaudhuri & Elsa Callen & Xia Ding & Ewa Gogola & Alexandra A. Duarte & Ji-Eun Lee & Nancy Wong & Vanessa Lafarga & Jennifer A. Calvo & Nicholas J. Panzarino & Sam John & Amanda Day & Anna V, 2016. "Erratum: Replication fork stability confers chemoresistance in BRCA-deficient cells," Nature, Nature, vol. 539(7629), pages 456-456, November.
    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. 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.
    2. Cuige Zhu & Mari Iwase & Ziqian Li & Faliang Wang & Annabel Quinet & Alessandro Vindigni & Jieya Shao, 2022. "Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Ramona N. Moro & Uddipta Biswas & Suhas S. Kharat & Filip D. Duzanic & Prosun Das & Maria Stavrou & Maria C. Raso & Raimundo Freire & Arnab Ray Chaudhuri & Shyam K. Sharan & Lorenza Penengo, 2023. "Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. 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.
    5. Anastasia Hale & Ashna Dhoonmoon & Joshua Straka & Claudia M. Nicolae & George-Lucian Moldovan, 2023. "Multi-step processing of replication stress-derived nascent strand DNA gaps by MRE11 and EXO1 nucleases," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Inés Paniagua & Zainab Tayeh & Mattia Falcone & Santiago Hernández Pérez & Aurora Cerutti & Jacqueline J. L. Jacobs, 2022. "MAD2L2 promotes replication fork protection and recovery in a shieldin-independent and REV3L-dependent manner," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. 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.
    8. Maria Dilia Palumbieri & Chiara Merigliano & Daniel González-Acosta & Danina Kuster & Jana Krietsch & Henriette Stoy & Thomas Känel & Svenja Ulferts & Bettina Welter & Joël Frey & Cyril Doerdelmann & , 2023. "Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    9. Ashna Dhoonmoon & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    10. Tanay Thakar & Ashna Dhoonmoon & Joshua Straka & Emily M. Schleicher & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "Lagging strand gap suppression connects BRCA-mediated fork protection to nucleosome assembly through PCNA-dependent CAF-1 recycling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    11. Rishi Kumar Jaiswal & Kai-Hang Lei & Megan Chastain & Yuan Wang & Olga Shiva & Shan Li & Zhongsheng You & Peter Chi & Weihang Chai, 2023. "CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    12. Youngho Kwon & Heike Rösner & Weixing Zhao & Platon Selemenakis & Zhuoling He & Ajinkya S. Kawale & Jeffrey N. Katz & Cody M. Rogers & Francisco E. Neal & Aida Badamchi Shabestari & Valdemaras Petrosi, 2023. "DNA binding and RAD51 engagement by the BRCA2 C-terminus orchestrate DNA repair and replication fork preservation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    13. Nikolaos Parisis & Pablo D. Dans & Muhammad Jbara & Balveer Singh & Diane Schausi-Tiffoche & Diego Molina-Serrano & Isabelle Brun-Heath & Denisa Hendrychová & Suman Kumar Maity & Diana Buitrago & Rafa, 2023. "Histone H3 serine-57 is a CHK1 substrate whose phosphorylation affects DNA repair," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    14. George E. Ronson & Katarzyna Starowicz & Elizabeth J. Anthony & Ann Liza Piberger & Lucy C. Clarke & Alexander J. Garvin & Andrew D. Beggs & Celina M. Whalley & Matthew J. Edmonds & James F. J. Beesle, 2023. "Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Antonios Revythis & Anu Limbu & Christos Mikropoulos & Aruni Ghose & Elisabet Sanchez & Matin Sheriff & Stergios Boussios, 2022. "Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer," IJERPH, MDPI, vol. 19(14), pages 1-19, July.
    16. 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.
    17. Vera M. Kissling & Giordano Reginato & Eliana Bianco & Kristina Kasaciunaite & Janny Tilma & Gea Cereghetti & Natalie Schindler & Sung Sik Lee & Raphaël Guérois & Brian Luke & Ralf Seidel & Petr Cejka, 2022. "Mre11-Rad50 oligomerization promotes DNA double-strand break repair," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Nagham Ghaddar & Yves Corda & Pierre Luciano & Martina Galli & Ylli Doksani & Vincent Géli, 2023. "The COMPASS subunit Spp1 protects nascent DNA at the Tus/Ter replication fork barrier by limiting DNA availability to nucleases," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    19. Natasha Ramakrishnan & Tyler M. Weaver & Lindsey N. Aubuchon & Ayda Woldegerima & Taylor Just & Kevin Song & Alessandro Vindigni & Bret D. Freudenthal & Priyanka Verma, 2024. "Nucleolytic processing of abasic sites underlies PARP inhibitor hypersensitivity in ALC1-deficient BRCA mutant cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    20. Ivo A. Hendriks & Sara C. Buch-Larsen & Evgeniia Prokhorova & Jonas D. Elsborg & Alexandra K.L.F.S. Rebak & Kang Zhu & Dragana Ahel & Claudia Lukas & Ivan Ahel & Michael L. Nielsen, 2021. "The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome," Nature Communications, Nature, vol. 12(1), pages 1-16, 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_s41467-024-46283-y. 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.