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G1 cyclin driven DNA replication.

ABSTRACT: The mitotic cell cycle is driven by Cyclin-Dependent Kinases (CDK). CDK activation requires the binding of activatory subunits termed cyclins. Different waves of cyclins are expressed during the cell cycle, enabling CDKs to trigger phase specific events. For instance, S phase cyclins promote the initiation of DNA replication but not chromosome segregation. There are at least 2 explanations for how such regulation is achieved. According to one of the visions, cyclins confer intrinsic substrate specificity to the CDK catalytic subunit. Alternatively a quantitative model has been proposed, according to which ever-increasing CDK activity is required to trigger cell cycle events from G1 to M. If a quantitative control prevails, then an early cyclin should trigger later cycle events if accumulated at high enough levels at the right time and place. We show here that a G1 phase cyclin bears the potential to trigger DNA replication and promote S and G2 phase specific transcription.

SUBMITTER: Palou R

PROVIDER: S-EPMC4825731 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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G1 cyclin driven DNA replication.

Palou Roger R Malik Asrar A Palou Gloria G Zeng Fanli F Ren Ping P Quintana David G DG

Cell cycle (Georgetown, Tex.) 20150101 24

The mitotic cell cycle is driven by Cyclin-Dependent Kinases (CDK). CDK activation requires the binding of activatory subunits termed cyclins. Different waves of cyclins are expressed during the cell cycle, enabling CDKs to trigger phase specific events. For instance, S phase cyclins promote the initiation of DNA replication but not chromosome segregation. There are at least 2 explanations for how such regulation is achieved. According to one of the visions, cyclins confer intrinsic substrate sp ...[more]

PMID: 26176277

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Project description:In response to DNA damage, eukaryotic cells initiate a complex signalling pathway, termed the DNA damage response (DDR), which coordinates cell cycle arrest with DNA repair. Studies have shown that oncogene-induced senescence, which provides a barrier to tumour development, involves activation of the DDR. Using a genome-wide RNA interference (RNAi) screen, we have identified 17 factors required for oncogenic BRAF to induce senescence in primary fibroblasts and melanocytes. One of these factors is an F-box protein, FBXO31, a candidate tumour suppressor encoded in 16q24.3, a region in which there is loss of heterozygosity in breast, ovarian, hepatocellular and prostate cancers. Here we study the cellular role of FBXO31, identify its target substrate and determine the basis for its growth inhibitory activity. We show that ectopic expression of FBXO31 acts through a proteasome-directed pathway to mediate the degradation of cyclin D1, an important regulator of progression from G1 to S phase, resulting in arrest in G1. Cyclin D1 degradation results from a direct interaction with FBXO31 and is dependent on the F-box motif of FBXO31 and phosphorylation of cyclin D1 at Thr 286, which is known to be required for cyclin D1 proteolysis. The involvement of the DDR in oncogene-induced senescence prompted us to investigate the role of FBXO31 in DNA repair. We find that DNA damage induced by gamma-irradiation results in increased FBXO31 levels, which requires phosphorylation of FBXO31 by the DDR-initiating kinase ATM. RNAi-mediated knockdown of FBXO31 prevents cells from undergoing efficient arrest in G1 after gamma-irradiation and markedly increases sensitivity to DNA damage. Finally, we show that a variety of DNA damaging agents all result in a large increase in FBXO31 levels, indicating that induction of FBXO31 is a general response to genotoxic stress. Our results reveal FBXO31 as a regulator of the G1/S transition that is specifically required for DNA damage-induced growth arrest.

Dataset Information

G1 cyclin driven DNA replication.

Publications

G1 cyclin driven DNA replication.

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