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p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice

Author

Listed:
  • Ross J. Hill

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Nazareno Bona

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Job Smink

    (Royal Netherlands Academy of Arts and Sciences (KNAW))

  • Hannah K. Webb

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Alastair Crisp

    (Cambridge Biomedical Campus, Francis Crick Avenue)

  • Juan I. Garaycoechea

    (Royal Netherlands Academy of Arts and Sciences (KNAW))

  • Gerry P. Crossan

    (Cambridge Biomedical Campus, Francis Crick Avenue)

Abstract

DNA repair deficiency can lead to segmental phenotypes in humans and mice, in which certain tissues lose homeostasis while others remain seemingly unaffected. This may be due to different tissues facing varying levels of damage or having different reliance on specific DNA repair pathways. However, we find that the cellular response to DNA damage determines different tissue-specific outcomes. Here, we use a mouse model of the human XPF-ERCC1 progeroid syndrome (XFE) caused by loss of DNA repair. We find that p53, a central regulator of the cellular response to DNA damage, regulates tissue dysfunction in Ercc1-/- mice in different ways. We show that ablation of p53 rescues the loss of hematopoietic stem cells, and has no effect on kidney, germ cell or brain dysfunction, but exacerbates liver pathology and polyploidisation. Mechanistically, we find that p53 ablation led to the loss of cell-cycle regulation in the liver, with reduced p21 expression. Eventually, p16/Cdkn2a expression is induced, serving as a fail-safe brake to proliferation in the absence of the p53-p21 axis. Taken together, our data show that distinct and tissue-specific functions of p53, in response to DNA damage, play a crucial role in regulating tissue-specific phenotypes.

Suggested Citation

  • Ross J. Hill & Nazareno Bona & Job Smink & Hannah K. Webb & Alastair Crisp & Juan I. Garaycoechea & Gerry P. Crossan, 2024. "p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46844-1
    DOI: 10.1038/s41467-024-46844-1
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    1. Laura J. Niedernhofer & George A. Garinis & Anja Raams & Astrid S. Lalai & Andria Rasile Robinson & Esther Appeldoorn & Hanny Odijk & Roos Oostendorp & Anwaar Ahmad & Wibeke van Leeuwen & Arjan F. The, 2006. "A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis," Nature, Nature, vol. 444(7122), pages 1038-1043, December.
    2. Tae-Won Kang & Tetyana Yevsa & Norman Woller & Lisa Hoenicke & Torsten Wuestefeld & Daniel Dauch & Anja Hohmeyer & Marcus Gereke & Ramona Rudalska & Anna Potapova & Marcus Iken & Mihael Vucur & Siegfr, 2011. "Senescence surveillance of pre-malignant hepatocytes limits liver cancer development," Nature, Nature, vol. 479(7374), pages 547-551, November.
    3. Yijie Gao & David O. Ferguson & Wei Xie & John P. Manis & JoAnn Sekiguchi & Karen M. Frank & Jayanta Chaudhuri & James Horner & Ronald A. DePinho & Frederick W. Alt, 2000. "Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development," Nature, Nature, vol. 404(6780), pages 897-900, April.
    4. Ivan Ahel & Ulrich Rass & Sherif F. El-Khamisy & Sachin Katyal & Paula M. Clements & Peter J. McKinnon & Keith W. Caldecott & Stephen C. West, 2006. "The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates," Nature, Nature, vol. 443(7112), pages 713-716, October.
    5. Jacob Stewart-Ornstein & Yoshiko Iwamoto & Miles A. Miller & Mark A. Prytyskach & Stephane Ferretti & Philipp Holzer & Joerg Kallen & Pascal Furet & Ashwini Jambhekar & William C. Forrester & Ralph We, 2021. "p53 dynamics vary between tissues and are linked with radiation sensitivity," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    6. M. A. Christophorou & I. Ringshausen & A. J. Finch & L. Brown Swigart & G. I. Evan, 2006. "The pathological response to DNA damage does not contribute to p53-mediated tumour suppression," Nature, Nature, vol. 443(7108), pages 214-217, September.
    7. Andrew W. Duncan & Matthew H. Taylor & Raymond D. Hickey & Amy E. Hanlon Newell & Michelle L. Lenzi & Susan B. Olson & Milton J. Finegold & Markus Grompe, 2010. "The ploidy conveyor of mature hepatocytes as a source of genetic variation," Nature, Nature, vol. 467(7316), pages 707-710, October.
    8. W. P. Vermeij & M. E. T. Dollé & E. Reiling & D. Jaarsma & C. Payan-Gomez & C. R. Bombardieri & H. Wu & A. J. M. Roks & S. M. Botter & B. C. van der Eerden & S. A. Youssef & R. V. Kuiper & B. Nagaraja, 2016. "Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice," Nature, Nature, vol. 537(7620), pages 427-431, September.
    9. Darren J. Baker & Bennett G. Childs & Matej Durik & Melinde E. Wijers & Cynthia J. Sieben & Jian Zhong & Rachel A. Saltness & Karthik B. Jeganathan & Grace Casaclang Verzosa & Abdulmohammad Pezeshki &, 2016. "Naturally occurring p16Ink4a-positive cells shorten healthy lifespan," Nature, Nature, vol. 530(7589), pages 184-189, February.
    10. Juan I. Garaycoechea & Gerry P. Crossan & Frédéric Langevin & Lee Mulderrig & Sandra Louzada & Fentang Yang & Guillaume Guilbaud & Naomi Park & Sophie Roerink & Serena Nik-Zainal & Michael R. Stratton, 2018. "Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells," Nature, Nature, vol. 553(7687), pages 171-177, January.
    11. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
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