Abstract
Genotoxic stress causes proliferating cells to activate the DNA damage checkpoint, to assist DNA damage recovery by slowing cell cycle progression. Thus, to drive proliferation, cells must tolerate DNA damage and suppress the checkpoint response. However, the mechanism underlying this negative regulation of checkpoint activation is still elusive. We show that human Cyclin-Dependent-Kinases (CDKs) target the RAD9 subunit of the 9-1-1 checkpoint clamp on Thr292, to modulate DNA damage checkpoint activation. Thr292 phosphorylation on RAD9 creates a binding site for Polo-Like-Kinase1 (PLK1), which phosphorylates RAD9 on Thr313. These CDK-PLK1-dependent phosphorylations of RAD9 suppress checkpoint activation, therefore maintaining high DNA synthesis rates during DNA replication stress. Our results suggest that CDK locally initiates a PLK1-dependent signaling response that antagonizes the ability of the DNA damage checkpoint to detect DNA damage. These findings provide a mechanism for the suppression of DNA damage checkpoint signaling, to promote cell proliferation under genotoxic stress conditions.
Highlights
To proliferate and maintain the integrity of biological systems, cells possess the ability to overcome environmental stresses
To understand how CDK controls the DNA damage checkpoint, we focused on the human checkpoint protein RAD9, which forms a PCNA-like hetero-trimeric checkpoint clamp complex
These results indicated that the PLK1-dependent phosphorylation of the Thr313 residue of RAD9 phenocopies the T292A-mutated RAD9, and suggested that PLK1 acts downstream of CDK to control the dissociation of RAD9 from chromatin upon genotoxic stress
Summary
To proliferate and maintain the integrity of biological systems, cells possess the ability to overcome environmental stresses. When the DNA damage response is dominant, checkpoint signaling reduces the rate of S-phase progression by repressing late origin firing or by slowing the progression of individual replication forks Together, these events can reduce genomic instability in proliferating cells, and thereby provide tumor-suppressor functions (Iyer and Rhind, 2013; Zegerman and Diffley, 2009). Mammalian cells can enter mitosis even in the presence of DNA damage signals, such as g-H2AX foci (Deckbar et al, 2007; Ishikawa et al, 2010; Syljuåsen et al, 2006) In this sense, mammalian cells can somehow repress a DNA damage checkpoint mechanism to tolerate the DNA damage response in order to drive proliferation, and PLK1 exhibits the key pro-mitotic activity for this purpose. These results implied that the CDK-/PLK1-dependent control of DNA damage detection by RAD9 plays a crucial role in minimizing the DNA damage checkpoint response, helping to drive proliferation under conditions of DNA replicative stress
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