The DNA damage response links human squamous proliferation with differentiation

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.

Nucleotide depletion promotes cell fate transitions by inducing DNA replication stress

“…DNA damage has been linked to cell fate changes in several systems (Grow et al, 2021; Inomata et al, 2009; Kato et al, 2021; Molinuevo et al, 2020; Santos et al, 2014; Wang et al, 2012). To directly test whether DNA damage can cause differentiation in these cells, we used various DNA damaging agents.…”

Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

“…This would also fit with the induction of stress keratins (Supplementary File 3). In fact, it might be directly connected to the squamous differentiation phenotype, as keratinocytes are known to undergo differentiation in response to DNA damage and replication stress (Freije et al, 2014; Molinuevo et al, 2020).…”

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation

“…Epithelial tissue homeostasis is constantly challenged by exposure to pro-mutational injuries and, thus, robust protective mechanisms against malignant transformation are crucial. In this context, compelling evidence have shown that after genotoxic or oncogenic stress, epithelial cells activate a terminal differentiation program that has been proposed as a safeguard mechanism against oncogenic alterations [36][37][38] . Altogether, cell polarity and differentiation have been positioned as key tumor suppressive mechanisms and their disruption is considered a hallmark in epithelial cancers 33,39 .…”