Abstract
The intra-S-checkpoint is essential to control cell progression through S phase under normal conditions and in response to replication stress. When DNA lesions are detected, replication fork progression is blocked allowing time for repair to avoid genomic instability and the risk of cancer. DNA replication initiates at many origins of replication in eukaryotic cells, where a series of proteins form pre-replicative complexes (pre-RCs) that are activated to become pre-initiation complexes and ensure a single round of replication in each cell cycle. PLK1 plays an important role in the regulation of DNA replication, contributing to the regulation of pre-RCs formation by phosphorylating several proteins, under both normal and stress conditions. Here we report that PLK1 is ubiquitinated and degraded by SCFFBXW7α/proteasome. Moreover, we identified a new Cdc4 phosphodegron in PLK1, conserved from yeast to humans, whose mutation prevents PLK1 destruction. We established that endogenous SCFFBXW7α degrades PLK1 in the G1 and S phases of an unperturbed cell cycle and in S phase following UV irradiation. Furthermore, we showed that FBXW7α overexpression or UV irradiation prevented the loading of proteins onto chromatin to form pre-RCs and, accordingly, reduced cell proliferation. We conclude that PLK1 degradation mediated by SCFFBXW7α modulates the intra-S-phase checkpoint.
Highlights
FBXW7 is a tumor suppressor gene that is frequently inactivated in different types of cancer, including breast cancer, colon cancer and leukemia [1]
Our findings show that FBXW7α and Polo-like kinase 1 (PLK1) associate in intact cells
PLK1 is considered a proto-oncogene, whose overexpression is often observed in tumor cells and FBXW7α is a tumor suppressor whose mutation occurs in multiple neoplasms
Summary
FBXW7 is a tumor suppressor gene that is frequently inactivated in different types of cancer, including breast cancer, colon cancer and leukemia [1]. F-box proteins are responsible for recruiting specific substrates for ubiquitination and degradation [2]. Mammalian cells contain three FBXW7 isoforms, FBXW7α, FBXW7β and FBXW7γ, that are produced by alternative splicing and localize to the nucleoplasm, cytoplasm and nucleolus, respectively [4, 5]. FBXW7α is the most highly expressed and stable FBXW7 isoform and expression levels of this protein do not vary significantly during the cell cycle [4, 6]. The FBXW7α transcript is ubiquitously expressed in all human tissues and is induced by the p53 tumor suppressor in response to DNA damage [7, 8]
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