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Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation

Author

Listed:
  • Rut Molinuevo

    (University of California
    University of California)

  • Julien Menendez

    (University of California
    University of California)

  • Kora Cadle

    (University of California)

  • Nabeela Ariqat

    (University of California)

  • Marie Klaire Choy

    (University of California)

  • Cayla Lagousis

    (University of California)

  • Gwen Thomas

    (University of California)

  • Catherine Strietzel

    (Zoetis Inc.)

  • J. W. Bubolz

    (Zoetis Inc.)

  • Lindsay Hinck

    (University of California
    University of California)

Abstract

Lactation insufficiency affects many women worldwide. During lactation, a large portion of mammary gland alveolar cells become polyploid, but how these cells balance the hyperproliferation occurring during normal alveologenesis with terminal differentiation required for lactation is unknown. Here, we show that DNA damage accumulates due to replication stress during pregnancy, activating the DNA damage response. Modulation of DNA damage levels in vivo by intraductal injections of nucleosides or DNA damaging agents reveals that the degree of DNA damage accumulated during pregnancy governs endoreplication and milk production. We identify a mechanism involving early mitotic arrest through CDK1 inactivation, resulting in a heterogeneous alveolar population with regards to ploidy and nuclei number. The inactivation of CDK1 is mediated by the DNA damage response kinase WEE1 with homozygous loss of Wee1 resulting in decreased endoreplication, alveologenesis and milk production. Thus, we propose that the DNA damage response to replication stress couples proliferation and endoreplication during mammary gland alveologenesis. Our study sheds light on mechanisms governing lactogenesis and identifies non-hormonal means for increasing milk production.

Suggested Citation

  • Rut Molinuevo & Julien Menendez & Kora Cadle & Nabeela Ariqat & Marie Klaire Choy & Cayla Lagousis & Gwen Thomas & Catherine Strietzel & J. W. Bubolz & Lindsay Hinck, 2024. "Physiological DNA damage promotes functional endoreplication of mammary gland alveolar cells during lactation," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47668-9
    DOI: 10.1038/s41467-024-47668-9
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    References listed on IDEAS

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