UHRF1 is required for basal stem cell proliferation in response to airway injury.
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.
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https://hdl.handle.net/10161/15358Published Version (Please cite this version)
10.1038/celldisc.2017.19Publication Info
Xiang, Handan; Yuan, Lifeng; Gao, Xia; Alexander, Peter B; Lopez, Omar; Lau, Calvin;
... Wang, Xiao-Fan (2017). UHRF1 is required for basal stem cell proliferation in response to airway injury.
Cell Discov, 3. pp. 17019. 10.1038/celldisc.2017.19. Retrieved from https://hdl.handle.net/10161/15358.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Qi-Jing Li
Adjunct Associate Professor in the Department of Immunology
Recent clinical success in cancer immunotherapy, including immune checkpoint blockades
and chimeric antigen receptor T cells, have settled a long-debated question in the
field: whether tumors can be recognized and eliminated by our own immune system, specifically,
the T lymphocyte. Meanwhile, current limitations of these advanced treatments pinpoint
fundamental knowledge deficits in basic T cell biology, especially in the context
of tumor-carrying patients. Aiming to develop new immunotherapi
Xiao-Fan Wang
Donald and Elizabeth Cooke Distinguished Professor of Cancer Research, in the School
of Medicine
The current research in the Wang laboratory mainly focuses on the elucidation of molecular
nature and signaling mechanisms associated with the initiation of cellular senescence.
In addition, we continue to study changes in tumor microenvironment that promotes
tumor progression and metastasis, particularly how tumor cells interact with the immune
system. Ultimately, we hope that our studies in these areas to lead to the development
of novel therapeutics for the treatment of various types of human
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