Rut Molinuevo, Ana Freije, Lizbeth Contreras, Juan R. Sanz, Alberto Gandarillas
Molinuevo et al. show a novel control of epidermoid
differentiation by the DNA damage response signals and propose a model
for automatic cleansing of stratified self-renewal epithelia facing
genotoxic agents.
doi: 10.1083/jcb.202001063.
The DNA damage response links human squamous proliferation with differentiation
Affiliations
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.
Article
October 01 2020
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