Online ahead of print.
p21CIP1 controls the squamous differentiation response to replication stress
Affiliations
- PMID: 33097856
- DOI: 10.1038/s41388-020-01520-8
Abstract
The control of cell fate is critical to homeostasis and cancer.
Cell cycle cdk inhibitor p21CIP1 has a central and paradoxical role in
the regulatory crossroads leading to senescence, apoptosis, or
differentiation. p21 is an essential target of tumor suppressor p53, but
it also is regulated independently. In squamous self-renewal epithelia
continuously exposed to mutagenesis, p21 controls cell fate by
mechanisms still intriguing. We previously identified a novel epidermoid
DNA damage-differentiation response. We here show that p21 intervenes
in the mitosis block that is required for the squamous differentiation
response to cell cycle deregulation and replication stress. The
inactivation of endogenous p21 in human primary keratinocytes alleviated
the differentiation response to oncogenic loss of p53 or overexpression
of the DNA replication major regulator Cyclin E. The bypass of
p21-induced mitotic block involving upregulation of Cyclin B allowed DNA
damaged cells to escape differentiation and continue to proliferate. In
addition, loss of p21 drove keratinocytes from differentiation to
apoptosis upon moderate UV irradiation. The results show that p21 is
required to drive keratinocytes towards differentiation in response to
genomic stress and shed light into its dual and paradoxical role in
carcinogenesis.
