Veronique A. J. Smits

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The cyclin-dependent kinase inhibitor p21 is required for a sustained G(2) arrest after activation of the DNA damage checkpoint. Here we have addressed the mechanism by which p21 can contribute to this arrest in G(2). We show that p21 blocks the activating phosphorylation of Cdc2 on Thr(161). p21 does not interfere with the dephosphorylation of two(More)
BACKGROUND Checkpoint signaling pathways are of crucial importance for the maintenance of genomic integrity. Within these pathways, the effector kinase Chk1 plays a central role in mediating cell-cycle arrest in response to DNA damage, and it does so by phosphorylating key cell-cycle regulators. RESULTS By investigating the subcellular distribution of(More)
Tight regulation of cell cycle progression is essential for the maintenance of genomic integrity. The orderly progression from one cell cycle phase to the other is mediated by timed activation of distinct cyclin/cdk complexes. For example, onset of mitosis is regulated by the activation of cyclin B/cdc2 and this event is controlled by several cell cycle(More)
Cell cycle checkpoints maintain genomic integrity by delaying cell division in the presence of DNA damage or replication problems. A crucial player in this process is the ATR kinase. The rapid localisation of ATR to sites of genotoxic stress and the central role of this kinase in the checkpoint response lead to the suggestion that ATR functions as a sensor(More)
The transcription/translation feedback loop-based molecular oscillator underlying the generation of circadian gene expression is preserved in almost all organisms. Interestingly, the animal circadian clock proteins CRYPTOCHROME (CRY), PERIOD (PER) and TIMELESS (TIM) are strongly conserved at the amino acid level through evolution. Within this evolutionary(More)
Chk1, an essential checkpoint kinase in the DNA damage response pathway (DDR), is tightly regulated by both ATR-dependent phosphorylation and proteasome-mediated degradation. Here we identify ubiquitin hydrolase USP7 as a novel regulator of Chk1 protein stability. USP7 was shown before to regulate other DDR proteins such as p53, Hdm2 and Claspin, an adaptor(More)
The Rad9/Rad1/Hus1 complex functions to facilitate the ATR-mediated phosphorylation of several substrates that control the checkpoint arrest induced by DNA damage. Here we show that in response to genotoxic stress induced by different types of damaging agents, Rad9 rapidly relocalized to sites of single stranded DNA, as visualized by discrete nuclear foci(More)
The ATR-Chk1 checkpoint pathway is activated by UV-induced DNA lesions and replication stress. Little was known about the spatio and temporal behaviour of the proteins involved, and we, therefore, examined the behaviour of the ATRIP-ATR and Rad9-Rad1-Hus1 putative DNA damage sensor complexes and the downstream effector kinase Chk1. We developed assays for(More)
Lithium can interfere with embryonal development in a variety of organisms. We investigated the effect of lithium on the proliferation of early embryonal cells. [3H]Thymidine incorporation of non-committed mouse P19 embryonal carcinoma cells was inhibited by lithium treatment. Similar effects were seen in a variety of other cells. This growth inhibition(More)
Polo-like kinases play multiple roles in different phases of mitosis. We have recently shown that the mammalian polo-like kinase, Plk1, is inhibited in response to DNA damage and that this inhibition may lead to cell cycle arrests at multiple points in mitosis. Here we have investigated the role of the checkpoint kinases ATM (ataxia telangiectasia mutated)(More)