Abstract
Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration.
Highlights
Cellular senescence represents a fundamental cell fate that has critical physiological roles in development, stem cell biology and wound healing, and pathological roles in tumorigenesis and aging [1,2,3,4,5,6,7]
Depletion of HELLS had no significant effect on human bronchial epithelial (HBE) cell senescence as measured by Edu incorporation and SA-β-Gal staining, which is consistent with previous findings in human fibroblasts [22]
UHRF1 knockdown resulted in major impairments in cell growth (Figure 1f), mimicking the induction of cellular senescence triggered by epidermal growth factor receptor inhibition
Summary
Cellular senescence represents a fundamental cell fate that has critical physiological roles in development, stem cell biology and wound healing, and pathological roles in tumorigenesis and aging [1,2,3,4,5,6,7]. Immunohistochemistry analysis of airway epithelium has revealed that basal cells are cytokeratin 5 (KRT5) positive [12] Those KRT5+ basal stem cells remain quiescent at steady state, but upon injury they replenish the wound by self-renewal and give rise to early progenitor cells to further differentiate into luminal cells to reconstruct to the homeostatic state. This regeneration process is precisely controlled in a spatio-temporal manner, and disruption of the balance between basal cell proliferation and differentiation invariably results in pathological conditions, such as chronic obstructive pulmonary disease [13]. Discovery of the underlying mechanisms of epithelium regeneration by airway basal cells could shed light on the etiology of relevant respiratory diseases
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