Abstract
The DNA-PK maintains cell survival when DNA damage occurs. In addition, aberrant activation of the DNA-PK induces centrosome amplification, suggesting additional roles for this kinase. Here, we showed that the DNA-PK-p53 cascade induced primary cilia formation (ciliogenesis), thus maintaining the DNA damage response under genotoxic stress. Treatment with genotoxic drugs (etoposide, neocarzinostatin, hydroxyurea, or cisplatin) led to ciliogenesis in human retina (RPE1), trophoblast (HTR8), lung (A459), and mouse Leydig progenitor (TM3) cell lines. Upon genotoxic stress, several DNA damage signaling were activated, but only the DNA-PK-p53 cascade contributed to ciliogenesis, as pharmacological inhibition or genetic depletion of this pathway decreased genotoxic stress-induced ciliogenesis. Interestingly, in addition to localizing to the nucleus, activated DNA-PK localized to the base of the primary cilium (mother centriole) and daughter centriole. Genotoxic stress also induced autophagy. Inhibition of autophagy initiation or lysosomal degradation or depletion of ATG7 decreased genotoxic stress-induced ciliogenesis. Besides, inhibition of ciliogenesis by depletion of IFT88 or CEP164 attenuated the genotoxic stress-induced DNA damage response. Thus, our study uncovered the interplay among genotoxic stress, the primary cilium, and the DNA damage response.
Highlights
Cells are continuously exposed to several stresses from endogenous and exogenous sources
Human immortalized retina pigmented epithelial (RPE1) and mouse Leydig progenitor (TM3) cell lines were grown in Dulbecco’s modified Eagle medium (DMEM)-F12, human immortalized trophoblast (HTR8) cells were grown in Roswell Park Memorial Institute (RPMI)-1640 medium, and human adenocarcinomic human alveolar basal epithelial (A459) cells were grown in DMEM
We showed that genotoxic stress facilitated primary cilium formation via the DNA-PK-p53 cascade and autophagy
Summary
Cells are continuously exposed to several stresses from endogenous and exogenous sources. The centrosome is composed of two centrioles, the mother and daughter centrioles, and surrounding pericentriolar material [8] and is the main microtubule organizing center for orchestrating microtubule arrays and the mitotic apparatus It serves as the base for primary cilium growth [9]. The primary cilium is an immotile, microtubule-based protrusion from the mother centriole that mainly functions as a cellular antenna to sense environmental signaling [10] This protrusion is composed of a central microtubule-based axoneme and the surrounding ciliary membrane. Autophagy is a lysosomal degradation process whereby cells degrade and reutilize old organelles and proteins to maintain metabolic homeostasis [12] It participates in ciliogenesis [13]. We showed that the DNA-PK-p53 cascade induced primary cilia formation, maintaining the DNA damage response under genotoxic stress. Our study uncovered the interplay among genotoxic stress, the primary cilium, and the DNA damage response
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