Distinct roles for cyclins E and A during DNA replication complex assembly and activation

Coverley, Dawn; Laman, Heike; Laskey, Ronald A.

doi:10.1038/ncb813

Cited by 272 publications

(296 citation statements)

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“…Cyclin E is regulated by E2F and controls DNA replication at the G1/S transition, stimulating the assembly of replication complexes and licensing of replication origins, whereas cyclin A activates origin firing and DNA synthesis [40]. Substrate specificities of cyclins E and A overlap [41], which accounts for the participation of both cyclins to SAMHD1 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

et al. 2018

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SAMHD1 is the major catabolic enzyme regulating the intracellular concentrations of DNA precursors (dNTPs). The S-phase kinase CDK2-cyclinA phosphorylates SAMHD1 at Thr-592. How this modification affects SAMHD1 function is highly debated. We investigated the role of endogenous SAMHD1 phosphorylation during the cell cycle. Thr-592 phosphorylation occurs first at the G1/S border and is removed during mitotic exit parallel with Thr-phosphorylations of most CDK1 targets. Differential sensitivity to the phosphatase inhibitor okadaic acid suggested different involvement of the PP1 and PP2 families dependent upon the time of the cell cycle. SAMHD1 turn-over indicates that Thr-592 phosphorylation does not cause rapid protein degradation. Furthermore, SAMHD1 influenced the size of the four dNTP pools independently of its phosphorylation. Our findings reveal that SAMHD1 is active during the entire cell cycle and performs an important regulatory role during S-phase by contributing with ribonucleotide reductase to maintain dNTP pool balance for proper DNA replication.

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Section: Discussionmentioning

confidence: 99%

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

et al. 2018

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“…These data suggest that in the context of adenomatogenesis overexpression and/or deregulation of hyperactive Cyclin E1-associated functions may affect early tumor progression. These functions include uncontrolled cell-cycle entry, the induction of aneuploidy (42), CIN (43) and defects in the assembly of the mini chromosome maintenance complex resulting in premature mitosis entry (44,45).…”

Section: Discussionmentioning

confidence: 99%

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Cheasley

Pereira

Sampurno

et al. 2015

Molecular Cancer Research

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Cyclin E1 is essential for the reentry of quiescent cells into the cell cycle. When hypomorphic mutant Myb mice (Myb Plt4 ) were examined, it was noted that Cyclin E1 (Ccne1) expression was reduced. Furthermore, the induction of Ccne1 in recovering intestinal epithelia following radiation-induced damage was ablated in Myb-mutant mice. These data prompted us to investigate whether Myb directly regulated Ccne1 and to examine whether elevated Myb in colorectal cancer is responsible for Cyclin E1-driven tumor growth. Here, it was found that Myb/ MYB and Ccne1/CCNE1 expressions were coupled in both mouse and human adenomas. In addition, the low molecular weight Cyclin E1 was the predominant form in intestinal crypts and adenomatous polyposis coli (Apc)-mutant adenomas. Chromatin immunoprecipitation (ChIP) analysis confirmed that Myb bound directly to the Ccne1 promoter and regulated its endogenous expression. In contrast, Myb Plt4 served as a dominant-negative factor that inhibited wild-type Myb and this was not apparently compensated for by the transcription factor E2F1 in intestinal epithelial cells. Myb Plt4/Plt4 mice died prematurely on an Apc Min/þ background associated with hematopoietic defects, including a myelodysplasia; nevertheless, Apc Min/þ mice were protected from intestinal tumorigenesis when crossed to Myb Plt4/þ mice. Knockdown of CCNE1 transcript in murine colorectal cancer cells stabilized chromosome ploidy and decreased tumor formation. These data suggest that Cyclin E1 expression is Myb dependent in normal and transformed intestinal epithelial cells, consistent with a cell-cycle progression and chromosome instability role in cancer.Implications: This study demonstrates that Myb regulates Cyclin E1 expression in normal gastrointestinal tract epithelial cells and is required during intestinal tumorigenesis. Mol Cancer Res; 13(8); 1185-96. Ó2015 AACR.

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“…Further increases of Cdk2/cyclin A activity are then proposed to fire replication origins. In this system, Cdk2/ cyclin E seems to be unable to trigger replication itself (Coverley et al, 2002). In contrast, cyclin E is normally essential for DNA replication in Drosophila embryos, and cyclin A is not required.…”

Section: Cdk/cyclin a Does Not Need To Be Concentrated Within Nuclei mentioning

confidence: 99%

“…One recent report, however, used an in vitro system based on G 1 nuclei and cytoplasm from mammalian cells, supplemented with relevant recombinant proteins, to probe the functions of the two cyclin-dependent kinases. It was proposed that at least during the transition into S phase from the G 1 phase block imposed by serum withdrawal, cyclin Eand cyclin A-dependent kinases execute sequential and separate functions (Coverley et al, 2002). According to these authors, cyclin E "opens a window of opportunity" for replication complex assembly, which is then closed by the activation of cyclin A.…”

Section: Molecular Biology Of the Cell 4398mentioning

confidence: 99%

Identification of the Nuclear Localization Signal inXenopusCyclin E and Analysis of Its Role in Replication and Mitosis

Moore

Kornbluth

Hunt

2002

MBoC

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Cyclin-dependent kinase (Cdk)2/cyclin E is imported into nuclei assembled in Xenopus egg extracts by a pathway that requires importin-␣ and -␤. Here, we identify a basic nuclear localization sequence (NLS) in the N-terminus of Xenopus cyclin E. Mutation of the NLS eliminated nuclear accumulation of both cyclin E and Cdk2, and such versions of cyclin E were unable to trigger DNA replication. Addition of a heterologous NLS from SV40 large T antigen restored both nuclear targeting of Cdk2/cyclin E and DNA replication. We present evidence indicating that Cdk2/cyclin E complexes must become highly concentrated within nuclei to support replication and find that cyclin A can trigger replication at much lower intranuclear concentrations. We confirmed that depletion of endogenous cyclin E increases the concentration of cyclin B necessary to promote entry into mitosis. In contrast to its inability to promote DNA replication, cyclin E lacking its NLS was able to cooperate with cyclin B in promoting mitotic entry. INTRODUCTIONCyclin-dependent kinases (Cdks) are vital for the initiation of both the major events of the eukaryotic cell cycle: the duplication of the genome in S phase and its segregation to two daughter cells during mitosis. In animal cells, several families of Cdks and cyclins have roles in cell cycle control. d-type cyclins complexed to Cdk4/Cdk6 regulate the decision to divide or differentiate, Cdk2/cyclin E and Cdk2/ cyclin A collaborate to initiate the events of S phase, and Cdk/cyclin A and Cdk1/cyclin B combine forces to trigger the wholesale reorganization of cellular components at mitosis (Girard et al., 1991;Pagano et al., 1992;Ohtsubo et al., 1995;Furuno et al., 1999;Hu et al., 2001;Nigg, 2001).Cdk/cyclin complexes are regulated by multiple mechanisms that ensure that they execute their functions at the correct time (Morgan, 1997); ubiquitylation and proteolysis of cyclins A and B are critical for M-phase exit (Wheatley et al., 1997;den Elzen and Pines, 2001; Geley et al., 2001), whereas defects in cyclin E proteolysis may be associated with certain cancers (Strohmaier et al., 2001). The subcellular localization of Cdk/cyclin complexes is also critical for faithful cell cycle control (Pines and Hunter, 1991;Hagting et al., 1998;Toyoshima et al., 1998;Pines, 1999;Alt et al., 2000;Draviam et al., 2001), and some progress has been made in identifying the mechanisms responsible, in particular those used by Cdk/cyclin complexes to shuttle between the cytoplasm and nucleus (Yang et al., 1998;Hagting et al., 1999;Moore et al., 1999;Takizawa et al., 1999). In this article, we focus attention on the mechanism and relevance of nuclear localization for the function of Cdk2/cyclin E in Xenopus egg extracts.Xenopus egg extracts have proved useful for studying the functions of Cdk/cyclin complexes in cell cycle control. Extracts exhibit excellent synchrony and faithfully recapitulate both S-phase and M-phase processes in vitro. Moreover, it is possible to manipulate their contents by depletion or addition of protei...

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Distinct roles for cyclins E and A during DNA replication complex assembly and activation

Cited by 272 publications

References 32 publications

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592

Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis

Identification of the Nuclear Localization Signal inXenopusCyclin E and Analysis of Its Role in Replication and Mitosis

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