The DNA damage response links human squamous proliferation with differentiation.

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  • Additional Information
    • Source:
      Publisher: Rockefeller University Press Country of Publication: United States NLM ID: 0375356 Publication Model: Print Cited Medium: Internet ISSN: 1540-8140 (Electronic) Linking ISSN: 00219525 NLM ISO Abbreviation: J Cell Biol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York : Rockefeller University Press
    • Subject Terms:
      Cell Differentiation* ; Cell Proliferation* ; DNA Damage*; Ataxia Telangiectasia Mutated Proteins/*metabolism ; Epithelial Cells/*cytology ; Keratinocytes/*cytology; Epithelial Cells/metabolism ; Histones ; Humans ; Keratinocytes/metabolism ; Phosphorylation ; Signal Transduction
    • Abstract:
      How rapid cell multiplication leads to cell differentiation in developing tissues is still enigmatic. This question is central to morphogenesis, cell number control, and homeostasis. Self-renewal epidermoid epithelia are continuously exposed to mutagens and are the most common target of cancer. Unknown mechanisms commit rapidly proliferating cells to post-mitotic terminal differentiation. We have over-activated or inhibited the endogenous DNA damage response (DDR) pathways by combinations of activating TopBP1 protein, specific shRNAs, or chemical inhibitors for ATR, ATM, and/or DNA-PK. The results dissect and demonstrate that these signals control keratinocyte differentiation in proliferating cells independently of actual DNA damage. The DDR limits keratinocyte multiplication upon hyperproliferative stimuli. Moreover, knocking down H2AX, a common target of the DDR pathways, inhibits the epidermoid phenotype. The results altogether show that the DDR is required to maintain the balance proliferation differentiation and suggest that is part of the squamous program. We propose a homeostatic model where genetic damage is automatically and continuously cleansed by cell-autonomous mechanisms.
      (© 2020 Molinuevo et al.)
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    • Accession Number:
      0 (Histones)
      EC 2.7.11.1 (ATR protein, human)
      EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins)
    • Publication Date:
      Date Created: 20201002 Date Completed: 20210330 Latest Revision: 20210502
    • Publication Date:
      20240829
    • Accession Number:
      PMC7534927
    • Accession Number:
      10.1083/jcb.202001063
    • Accession Number:
      33007086