Abstract
The protein kinase C (PKC) superfamily plays key regulatory roles in numerous cellular processes. Saccharomyces cerevisiae contains a single PKC, Pkc1, whose main function is cell wall integrity maintenance. In this work, we connect the Pkc1 protein to the maintenance of genome integrity in response to genotoxic stresses. Pkc1 and its kinase activity are necessary for the phosphorylation of checkpoint kinase Rad53, histone H2A and Xrs2 protein after deoxyribonucleic acid (DNA) damage, indicating that Pkc1 is required for activation of checkpoint kinases Mec1 and Tel1. Furthermore, Pkc1 electrophoretic mobility is delayed after inducing DNA damage, which reflects that Pkc1 is post-translationally modified. This modification is a phosphorylation event mediated by Tel1. The expression of different mammalian PKC isoforms at the endogenous level in yeast pkc1 mutant cells revealed that PKCδ is able to activate the DNA integrity checkpoint. Finally, downregulation of PKCδ activity in HeLa cells caused a defective activation of checkpoint kinase Chk2 when DNA damage was induced. Our results indicate that the control of the DNA integrity checkpoint by PKC is a mechanism conserved from yeast to humans.
Highlights
Genome integrity maintenance is a major concern for cellular physiology
It is important to note that the activation of Rad53 was restored in the pkc1 mutant cells transformed with a centromeric plasmid containing the PKC1 gene (Figure 1B), which confirms that Pkc1 activity is required for checkpoint kinase Rad53 activation in response to deoxyribonucleic acid (DNA) damage
Pkc1 mutant strain is hypersensitive to different genotoxic agents such as HU, bleomycin, methyl metanosulfonate (MMS) and 4-nitroquinoline 1-oxide (4NQO) [38,42,43]
Summary
Genome integrity maintenance is a major concern for cellular physiology. Genetic material is constantly exposed to damage. It has been estimated that every single cell in the human body is subjected to several thousands of deoxyribonucleic acid (DNA) lesions every day [1,2] Some of those aberrations are due to physiological processes, such as replicative errors, deficient activity of some enzymes or reactive oxygen species. DNA damage is produced by external physical and chemical sources To counteract such threats, cells have evolved a mechanism that detects damage, transduces the signal and triggers an accurate cellular response to maintain genome stability. Cells have evolved a mechanism that detects damage, transduces the signal and triggers an accurate cellular response to maintain genome stability This surveillance mechanism is known as the DNA integrity checkpoint [3,4]. Proper checkpoint functioning is crucial for cell viability and for preventing diseases like cancer
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