IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-023-44209-8.html
   My bibliography  Save this article

Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation

Author

Listed:
  • Simon D. Schwarz

    (University of Basel)

  • Jianming Xu

    (University of Basel
    University of Zurich)

  • Kapila Gunasekera

    (University of Zurich
    University of Bern)

  • David Schürmann

    (University of Basel)

  • Cathrine B. Vågbø

    (Norwegian University of Science and Technology and St. Olavs Hospital)

  • Elena Ferrari

    (University of Zurich)

  • Geir Slupphaug

    (Norwegian University of Science and Technology and St. Olavs Hospital)

  • Michael O. Hottiger

    (University of Zurich)

  • Primo Schär

    (University of Basel)

  • Roland Steinacher

    (University of Basel
    ETH Zurich)

Abstract

The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) and DNA demethylation and have been implicated in epigenetic programming in early mammalian development. Recently, proteomic analyses identified BER proteins to be covalently poly-ADP-ribosylated by PARPs. The role of this posttranslational modification in the BER process is unknown. Here, we show that PARP1 senses AP-sites and SSBs generated during TET-TDG mediated active DNA demethylation and covalently attaches PAR to each BER protein engaged. Covalent PARylation dissociates BER proteins from DNA, which accelerates the completion of the repair process. Consistently, inhibition of PARylation in mESC resulted both in reduced locus-specific TET-TDG-targeted DNA demethylation, and in reduced general repair of random DNA damage. Our findings establish a critical function of covalent protein PARylation in coordinating molecular processes associated with dynamic DNA methylation.

Suggested Citation

  • Simon D. Schwarz & Jianming Xu & Kapila Gunasekera & David Schürmann & Cathrine B. Vågbø & Elena Ferrari & Geir Slupphaug & Michael O. Hottiger & Primo Schär & Roland Steinacher, 2024. "Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44209-8
    DOI: 10.1038/s41467-023-44209-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-44209-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-44209-8?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. Alain R. Weber & Claudia Krawczyk & Adam B. Robertson & Anna Kuśnierczyk & Cathrine B. Vågbø & David Schuermann & Arne Klungland & Primo Schär, 2016. "Biochemical reconstitution of TET1–TDG–BER-dependent active DNA demethylation reveals a highly coordinated mechanism," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    2. Marcin J. Suskiewicz & Florian Zobel & Tom E. H. Ogden & Pietro Fontana & Antonio Ariza & Ji-Chun Yang & Kang Zhu & Lily Bracken & William J. Hawthorne & Dragana Ahel & David Neuhaus & Ivan Ahel, 2020. "HPF1 completes the PARP active site for DNA damage-induced ADP-ribosylation," Nature, Nature, vol. 579(7800), pages 598-602, March.
    3. Huifen Cao & Lorena Salazar-García & Fan Gao & Thor Wahlestedt & Chun-Lin Wu & Xueer Han & Ye Cai & Dongyang Xu & Fang Wang & Lu Tang & Natalie Ricciardi & DingDing Cai & Huifang Wang & Mario P. S. Ch, 2019. "Novel approach reveals genomic landscapes of single-strand DNA breaks with nucleotide resolution in human cells," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    4. George E. Ronson & Ann Liza Piberger & Martin R. Higgs & Anna L. Olsen & Grant S. Stewart & Peter J. McHugh & Eva Petermann & Nicholas D. Lakin, 2018. "PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
    5. Wei Wu & Sarah E. Hill & William J. Nathan & Jacob Paiano & Elsa Callen & Dongpeng Wang & Kenta Shinoda & Niek Wietmarschen & Jennifer M. Colón-Mercado & Dali Zong & Raffaella Pace & Han-Yu Shih & Ste, 2021. "Neuronal enhancers are hotspots for DNA single-strand break repair," Nature, Nature, vol. 593(7859), pages 440-444, May.
    6. Paul Adrian Ginno & Dimos Gaidatzis & Angelika Feldmann & Leslie Hoerner & Dilek Imanci & Lukas Burger & Frederic Zilbermann & Antoine H. F. M. Peters & Frank Edenhofer & Sébastien A. Smallwood & Arna, 2020. "A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    7. 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.
    8. Hana Hanzlikova & Evgeniia Prokhorova & Katerina Krejcikova & Zuzana Cihlarova & Ilona Kalasova & Jan Kubovciak & Jana Sachova & Richard Hailstone & Jan Brazina & Shereen Ghosh & Sebahattin Cirak & Jo, 2020. "Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    9. Annika Krüger & Alexander Bürkle & Karin Hauser & Aswin Mangerich, 2020. "Real-time monitoring of PARP1-dependent PARylation by ATR-FTIR spectroscopy," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    10. Clifford D. Mol & Tadahide Izumi & Sankar Mitra & John A. Tainer, 2000. "DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination," Nature, Nature, vol. 403(6768), pages 451-456, January.
    11. Clifford D. Mol & Tadahide Izumi & Sankar Mitra & John A. Tainer, 2000. "Erratum: DNA-bound structures and mutants reveal abasic DNA binding by APE1 and DNA repair coordination," Nature, Nature, vol. 404(6777), pages 525-525, March.
    12. Rahul M. Kohli & Yi Zhang, 2013. "TET enzymes, TDG and the dynamics of DNA demethylation," Nature, Nature, vol. 502(7472), pages 472-479, October.
    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. 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.
    2. Lina Wang & Siru Li & Kai Wang & Na Wang & Qiaoling Liu & Zhen Sun & Li Wang & Lulu Wang & Quentin Liu & Chengli Song & Caigang Liu & Qingkai Yang, 2022. "DNA mechanical flexibility controls DNA potential to activate cGAS-mediated immune surveillance," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Pietro Fontana & Sara C. Buch-Larsen & Osamu Suyari & Rebecca Smith & Marcin J. Suskiewicz & Kira Schützenhofer & Antonio Ariza & Johannes Gregor Matthias Rack & Michael L. Nielsen & Ivan Ahel, 2023. "Serine ADP-ribosylation in Drosophila provides insights into the evolution of reversible ADP-ribosylation signalling," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Frederick Richards & Marta J. Llorca-Cardenosa & Jamie Langton & Sara C. Buch-Larsen & Noor F. Shamkhi & Abhishek Bharadwaj Sharma & Michael L. Nielsen & Nicholas D. Lakin, 2023. "Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Ye Cai & Huifen Cao & Fang Wang & Yufei Zhang & Philipp Kapranov, 2022. "Complex genomic patterns of abasic sites in mammalian DNA revealed by a high-resolution SSiNGLe-AP method," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    6. Tyler M. Weaver & Nicole M. Hoitsma & Jonah J. Spencer & Lokesh Gakhar & Nicholas J. Schnicker & Bret D. Freudenthal, 2022. "Structural basis for APE1 processing DNA damage in the nucleosome," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    7. Luka Bacic & Guillaume Gaullier & Jugal Mohapatra & Guanzhong Mao & Klaus Brackmann & Mikhail Panfilov & Glen Liszczak & Anton Sabantsev & Sebastian Deindl, 2024. "Asymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    8. Allegra Angeloni & Skye Fissette & Deniz Kaya & Jillian M. Hammond & Hasindu Gamaarachchi & Ira W. Deveson & Robert J. Klose & Weiming Li & Xiaotian Zhang & Ozren Bogdanovic, 2024. "Extensive DNA methylome rearrangement during early lamprey embryogenesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Steffen Mueller & Gail Dennison & Shujun Liu, 2021. "An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality," IJERPH, MDPI, vol. 18(13), pages 1-23, June.
    10. Marie-France Langelier & Ramya Billur & Aleksandr Sverzhinsky & Ben E. Black & John M. Pascal, 2021. "HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    11. Charlotte Blessing & Katja Apelt & Diana Heuvel & Claudia Gonzalez-Leal & Magdalena B. Rother & Melanie Woude & Román González-Prieto & Adi Yifrach & Avital Parnas & Rashmi G. Shah & Tia Tyrsett Kuo &, 2022. "XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Ozge Saatci & Metin Cetin & Meral Uner & Unal Metin Tokat & Ioulia Chatzistamou & Pelin Gulizar Ersan & Elodie Montaudon & Aytekin Akyol & Sercan Aksoy & Aysegul Uner & Elisabetta Marangoni & Mathew S, 2023. "Toxic PARP trapping upon cAMP-induced DNA damage reinstates the efficacy of endocrine therapy and CDK4/6 inhibitors in treatment-refractory ER+ breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    13. Yanbo Wang & W. Taylor Cottle & Haobo Wang & Momcilo Gavrilov & Roger S. Zou & Minh-Tam Pham & Srinivasan Yegnasubramanian & Scott Bailey & Taekjip Ha, 2022. "Achieving single nucleotide sensitivity in direct hybridization genome imaging," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    14. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Dalia Halawani & Yiqun Wang & Aarthi Ramakrishnan & Molly Estill & Xijing He & Li Shen & Roland H. Friedel & Hongyan Zou, 2023. "Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    16. Kosuke Yamaguchi & Xiaoying Chen & Brianna Rodgers & Fumihito Miura & Pavel Bashtrykov & Frédéric Bonhomme & Catalina Salinas-Luypaert & Deis Haxholli & Nicole Gutekunst & Bihter Özdemir Aygenli & Lau, 2024. "Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Qing Li & Jiansen Lu & Xidi Yin & Yunjian Chang & Chao Wang & Meng Yan & Li Feng & Yanbo Cheng & Yun Gao & Beiying Xu & Yao Zhang & Yingyi Wang & Guizhong Cui & Luang Xu & Yidi Sun & Rong Zeng & Yixue, 2023. "Base editing-mediated one-step inactivation of the Dnmt gene family reveals critical roles of DNA methylation during mouse gastrulation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    18. Liu Yang & San-Jian Yu & Qi Hong & Yu Yang & Zhi-Ming Shao, 2015. "Reduced Expression of TET1, TET2, TET3 and TDG mRNAs Are Associated with Poor Prognosis of Patients with Early Breast Cancer," PLOS ONE, Public Library of Science, vol. 10(7), pages 1-10, July.
    19. Letizia Pitto & Francesca Gorini & Fabrizio Bianchi & Elena Guzzolino, 2020. "New Insights into Mechanisms of Endocrine-Disrupting Chemicals in Thyroid Diseases: The Epigenetic Way," IJERPH, MDPI, vol. 17(21), pages 1-18, October.
    20. Megha Jhanji & Chintada Nageswara Rao & Jacob C. Massey & Marion C. Hope & Xueyan Zhou & C. Dirk Keene & Tao Ma & Michael D. Wyatt & Jason A. Stewart & Mathew Sajish, 2022. "Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration," Nature Communications, Nature, vol. 13(1), pages 1-17, 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_s41467-023-44209-8. 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.