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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
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    References listed on IDEAS

    as
    1. 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.
    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. 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.
    4. 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.
    5. 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.
    6. 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.
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