The DNA damage response links human squamous proliferation with differentiation
| Autor: | Lizbeth Contreras, Juan R Sanz, Ana Freije, Rut Molinuevo, Alberto Gandarillas |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Keratinocytes
DNA damage Cellular differentiation Cell Morphogenesis Endogeny Ataxia Telangiectasia Mutated Proteins Biology Development Article Histones 03 medical and health sciences 0302 clinical medicine Cell Signaling medicine Humans Phosphorylation 030304 developmental biology Cancer Cell Proliferation 0303 health sciences Cell Differentiation Epithelial Cells Cell Biology Phenotype Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis Keratinocyte Homeostasis Cell Cycle and Division DNA Damage Signal Transduction |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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