IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-024-55638-4.html
   My bibliography  Save this article

OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts

Author

Listed:
  • Mariarosaria Rosa

    (UPMC Hillman Cancer Center at the University of Pittsburgh)

  • Ryan P. Barnes

    (UPMC Hillman Cancer Center at the University of Pittsburgh
    University of Kansas Medical Center)

  • Ariana C. Detwiler

    (UPMC Hillman Cancer Center at the University of Pittsburgh)

  • Prasanth R. Nyalapatla

    (University of Pittsburgh)

  • Peter Wipf

    (UPMC Hillman Cancer Center at the University of Pittsburgh
    University of Pittsburgh)

  • Patricia L. Opresko

    (UPMC Hillman Cancer Center at the University of Pittsburgh
    University of Pittsburgh School of Medicine
    University of Pittsburgh School of Public Health)

Abstract

Telomeres are hypersensitive to the formation of the common oxidative lesion 8-oxoguanine (8oxoG), which impacts telomere stability and function. OGG1 and MUTYH glycosylases initiate base excision repair (BER) to remove 8oxoG or prevent mutation. Here, we show OGG1 loss or inhibition, or MUTYH loss, partially rescues telomeric 8oxoG-induced premature senescence and associated proinflammatory responses, while loss of both glycosylases causes a near complete rescue in human fibroblasts. Glycosylase deficiency also suppresses 8oxoG-induced telomere fragility and dysfunction, indicating that downstream single-stranded break (SSB) repair intermediates impair telomere replication. Preventing BER initiation suppresses PARylation and confers resistance to the synergistic effects of PARP inhibitors on 8oxoG-induced senescence. However, OGG1 activity is essential for preserving cell growth after chronic telomeric 8oxoG formation, whereas MUTYH promotes senescence to prevent chromosomal instability from unrepaired damage. Our studies reveal that inefficient completion of 8oxoG BER at telomeres triggers cellular senescence via SSB intermediates which disrupt telomere function.

Suggested Citation

  • Mariarosaria Rosa & Ryan P. Barnes & Ariana C. Detwiler & Prasanth R. Nyalapatla & Peter Wipf & Patricia L. Opresko, 2025. "OGG1 and MUTYH repair activities promote telomeric 8-oxoguanine induced senescence in human fibroblasts," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55638-4
    DOI: 10.1038/s41467-024-55638-4
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-55638-4
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-55638-4?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. 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.
    2. Diana Jurk & Caroline Wilson & João F. Passos & Fiona Oakley & Clara Correia-Melo & Laura Greaves & Gabriele Saretzki & Chris Fox & Conor Lawless & Rhys Anderson & Graeme Hewitt & Sylvia LF Pender & N, 2014. "Chronic inflammation induces telomere dysfunction and accelerates ageing in mice," Nature Communications, Nature, vol. 5(1), pages 1-14, September.
    3. Namrata Kumar & Arjan F. Theil & Vera Roginskaya & Yasmin Ali & Michael Calderon & Simon C. Watkins & Ryan P. Barnes & Patricia L. Opresko & Alex Pines & Hannes Lans & Wim Vermeulen & Bennett Houten, 2022. "Global and transcription-coupled repair of 8-oxoG is initiated by nucleotide excision repair proteins," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Graeme Hewitt & Diana Jurk & Francisco D.M. Marques & Clara Correia-Melo & Timothy Hardy & Agata Gackowska & Rhys Anderson & Morgan Taschuk & Jelena Mann & João F. Passos, 2012. "Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
    5. Ludmil B. Alexandrov & Jaegil Kim & Nicholas J. Haradhvala & Mi Ni Huang & Alvin Wei Tian Ng & Yang Wu & Arnoud Boot & Kyle R. Covington & Dmitry A. Gordenin & Erik N. Bergstrom & S. M. Ashiqul Islam , 2020. "The repertoire of mutational signatures in human cancer," Nature, Nature, vol. 578(7793), pages 94-101, February.
    6. Joe Nassour & Robert Radford & Adriana Correia & Javier Miralles Fusté & Brigitte Schoell & Anna Jauch & Reuben J. Shaw & Jan Karlseder, 2019. "Autophagic cell death restricts chromosomal instability during replicative crisis," Nature, Nature, vol. 565(7741), pages 659-663, January.
    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. Cameron Cordero & Kavi P. M. Mehta & Tyler M. Weaver & Justin A. Ling & Bret D. Freudenthal & David Cortez & Steven A. Roberts, 2024. "Contributing factors to the oxidation-induced mutational landscape in human cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Teresa Maria Rosaria Noviello & Anna Maria Giacomo & Francesca Pia Caruso & Alessia Covre & Roberta Mortarini & Giovanni Scala & Maria Claudia Costa & Sandra Coral & Wolf H. Fridman & Catherine Sautès, 2023. "Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. 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.
    4. Oriol Pich & Iker Reyes-Salazar & Abel Gonzalez-Perez & Nuria Lopez-Bigas, 2022. "Discovering the drivers of clonal hematopoiesis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. 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.
    6. Noah Sasa & Toshihiro Kishikawa & Masashi Mori & Rie Ito & Yumie Mizoro & Masami Suzuki & Hirotaka Eguchi & Hidenori Tanaka & Takahito Fukusumi & Motoyuki Suzuki & Yukinori Takenaka & Keisuke Nimura &, 2025. "Intratumor heterogeneity of HPV integration in HPV-associated head and neck cancer," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
    7. 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.
    8. Eline J. M. Bertrums & Jurrian K. Kanter & Lucca L. M. Derks & Mark Verheul & Laurianne Trabut & Markus J. Roosmalen & Henrik Hasle & Evangelia Antoniou & Dirk Reinhardt & Michael N. Dworzak & Nora Mü, 2024. "Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Benjamin A. Nacev & Francisco Sanchez-Vega & Shaleigh A. Smith & Cristina R. Antonescu & Evan Rosenbaum & Hongyu Shi & Cerise Tang & Nicholas D. Socci & Satshil Rana & Rodrigo Gularte-Mérida & Ahmet Z, 2022. "Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Timothy K. Turkalo & Antonio Maffia & Johannes J. Schabort & Samuel G. Regalado & Mital Bhakta & Marco Blanchette & Diana C. J. Spierings & Peter M. Lansdorp & Dirk Hockemeyer, 2023. "A non-genetic switch triggers alternative telomere lengthening and cellular immortalization in ATRX deficient cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Dillon S. McBride & Sofya K. Garushyants & John Franks & Andrew F. Magee & Steven H. Overend & Devra Huey & Amanda M. Williams & Seth A. Faith & Ahmed Kandeil & Sanja Trifkovic & Lance Miller & Trusha, 2023. "Accelerated evolution of SARS-CoV-2 in free-ranging white-tailed deer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Guidantonio Malagoli Tagliazucchi & Anna J. Wiecek & Eloise Withnell & Maria Secrier, 2023. "Genomic and microenvironmental heterogeneity shaping epithelial-to-mesenchymal trajectories in cancer," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    13. Ryan N. Ptashkin & Mark D. Ewalt & Gowtham Jayakumaran & Iwona Kiecka & Anita S. Bowman & JinJuan Yao & Jacklyn Casanova & Yun-Te David Lin & Kseniya Petrova-Drus & Abhinita S. Mohanty & Ruben Bacares, 2023. "Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    14. Erik Elias & Arman Ardalan & Markus Lindberg & Susanne E. Reinsbach & Andreas Muth & Ola Nilsson & Yvonne Arvidsson & Erik Larsson, 2021. "Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    15. Luan Nguyen & Arne Hoeck & Edwin Cuppen, 2022. "Machine learning-based tissue of origin classification for cancer of unknown primary diagnostics using genome-wide mutation features," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    16. Yoshitaka Sakamoto & Shuhei Miyake & Miho Oka & Akinori Kanai & Yosuke Kawai & Satoi Nagasawa & Yuichi Shiraishi & Katsushi Tokunaga & Takashi Kohno & Masahide Seki & Yutaka Suzuki & Ayako Suzuki, 2022. "Phasing analysis of lung cancer genomes using a long read sequencer," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    17. Stefan Harjes & Harikrishnan M. Kurup & Amanda E. Rieffer & Maitsetseg Bayarjargal & Jana Filitcheva & Yongdong Su & Tracy K. Hale & Vyacheslav V. Filichev & Elena Harjes & Reuben S. Harris & Geoffrey, 2023. "Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    18. Zhenhua Li & Huanbin Zhao & Wenjian Yang & Maud Maillard & Satoshi Yoshimura & Yu-Chih Hsiao & Xin Huang & Yoshihiro Gocho & Lauren Rowland & Anthony Brown & Landon Choi & Kristine R. Crews & Charles , 2025. "Molecular and pharmacological heterogeneity of ETV6::RUNX1 acute lymphoblastic leukemia," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    19. Minghao Li & Zicheng Zhang & Qianrong Wang & Yan Yi & Baosheng Li, 2022. "Integrated cohort of esophageal squamous cell cancer reveals genomic features underlying clinical characteristics," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    20. Shengli Li & Li Yuan & Zhi-Yuan Xu & Jing-Li Xu & Gui-Ping Chen & Xiaoqing Guan & Guang-Zhao Pan & Can Hu & Jinyun Dong & Yi-An Du & Li-Tao Yang & Mao-Wei Ni & Rui-Bin Jiang & Xiu Zhu & Hang Lv & Han-, 2023. "Integrative proteomic characterization of adenocarcinoma of esophagogastric junction," Nature Communications, Nature, vol. 14(1), pages 1-19, 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_s41467-024-55638-4. 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.