Key points are not available for this paper at this time.
Cyclin A and CDC25A are both activators of cyclin-dependent kinases (CDKs): cyclin A acts as an activating subunit of CDKs and CDC25A a phosphatase of the inhibitory phosphorylation sites of the CDKs. In this study, we uncovered an inverse relationship between the two CDK activators. As cyclin A is an essential gene, we generated a conditional silencing cell line using a combination of CRISPR-Cas9 and degron-tagged cyclin A. Destruction of cyclin A promoted an acute accumulation of CDC25A. The increase of CDC25A after cyclin A depletion occurred throughout the cell cycle and was independent on cell cycle delay caused by cyclin A deficiency. Moreover, we determined that the inverse relationship with cyclin A was specific for CDC25A and not for other CDC25 family members or kinases that regulate the same sites in CDKs. Unexpectedly, the upregulation of CDC25A was mainly caused by an increase in transcriptional activity instead of a change in the stability of the protein. Reversing the accumulation of CDC25A severely delayed G2–M in cyclin A-depleted cells. Taken together, these data provide evidence of a compensatory mechanism involving CDC25A that ensures timely mitotic entry at different levels of cyclin A. Cyclin A and CDC25A are both activators of cyclin-dependent kinases (CDKs): cyclin A acts as an activating subunit of CDKs and CDC25A a phosphatase of the inhibitory phosphorylation sites of the CDKs. In this study, we uncovered an inverse relationship between the two CDK activators. As cyclin A is an essential gene, we generated a conditional silencing cell line using a combination of CRISPR-Cas9 and degron-tagged cyclin A. Destruction of cyclin A promoted an acute accumulation of CDC25A. The increase of CDC25A after cyclin A depletion occurred throughout the cell cycle and was independent on cell cycle delay caused by cyclin A deficiency. Moreover, we determined that the inverse relationship with cyclin A was specific for CDC25A and not for other CDC25 family members or kinases that regulate the same sites in CDKs. Unexpectedly, the upregulation of CDC25A was mainly caused by an increase in transcriptional activity instead of a change in the stability of the protein. Reversing the accumulation of CDC25A severely delayed G2–M in cyclin A-depleted cells. Taken together, these data provide evidence of a compensatory mechanism involving CDC25A that ensures timely mitotic entry at different levels of cyclin A. The cell cycle is choreographed by an evolutionarily conserved engine composed of a family of protein kinases called cyclin-dependent kinases (CDKs) (1Poon R.Y.C. Cell cycle control: a system of interlinking oscillators.Methods Mol. Biol. 2021; 2329: 1-18Crossref PubMed Scopus (7) Google Scholar). The current paradigm states that in human cells, CDK1 is activated by the mitotic cyclins (cyclin A and B) and drives G2 cells into mitosis (2Fung T.K. Poon R.Y. A roller coaster ride with the mitotic cyclins.Semin. Cell Dev. Biol. 2005; 16: 335-342Crossref PubMed Scopus (142) Google Scholar). Another CDK family member, CDK2, associates mainly with cyclin E and cyclin A, and the complexes formed are critical for G1-S transition and in S phase, respectively (3Woo R.A. Poon R.Y. Cyclin-dependent kinases and S phase control in mammalian cells.Cell Cycle. 2003; 2: 316-324Crossref PubMed Scopus (178) Google Scholar). CDK4 and CDK6 are partners of cyclin D, functioning in G1–S transition before cyclin E–CDK2 (4Malumbres M. Cyclin-dependent kinases.Genome Biol. 2014; 15: 122Crossref PubMed Scopus (986) Google Scholar). The activities of CDKs are stringently regulated by protein–protein interactions and phosphorylation. For example, binding to a mitotic cyclin subunit is necessary for full activation of CDK1. On binding to cyclin B, the kinase activity of CDK1 is initially suppressed by inhibitory phosphorylation on CDK1T14/Y15 by MYT1 and WEE1 (5Ma H.T. Poon R.Y. How protein kinases co-ordinate mitosis in animal cells.Biochem. J. 2011; 435: 17-31Crossref PubMed Scopus (99) Google Scholar). At the end of G2, the stockpile of inactive cyclin B–CDK1 complexes is activated by members of the CDC25 dual-specificity phosphatase family (6Lindqvist A. Rodríguez-Bravo V. Medema R.H. The decision to enter mitosis: feedback and redundancy in the mitotic entry network.J. Cell Biol. 2009; 185: 193-202Crossref PubMed Scopus (431) Google Scholar). Active CDK1 then activates more CDC25 and inactivates WEE1 by directly phosphorylating these proteins. This autocatalytic loop enables rapid and complete activation of all the cyclin B–CDK1 complexes by an initially small amount of active CDK1. The presence of three isoforms of CDC25 (A, B, and C) differing in cell cycle regulation, localization, and mood of regulation suggests that they may play nonoverlapping roles in the cell cycle. CDC25A appears to be particularly important, at least in mice, as knockout of Cdc25A results in early embryonic lethality (7Ray D. Terao Y. Nimbalkar D. Hirai H. Osmundson E.C. Zou X. et al.Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice.Cancer Res. 2007; 67: 6605-6611Crossref PubMed Scopus (68) Google Scholar). By contrast, mice lacking both Cdc25B and Cdc25C are generally normal (8Ferguson A.M. White L.S. Donovan P.J. Piwnica-Worms H. Normal cell cycle and checkpoint responses in mice and cells lacking Cdc25B and Cdc25C protein phosphatases.Mol. Cell. Biol. 2005; 25: 2853-2860Crossref PubMed Scopus (124) Google Scholar). The prevailing view is that while CDC25B and CDC25C regulate mainly the G2–M cyclin–CDK complexes, CDC25A is involved in the control of both G1–S and G2–M cyclin–CDK pairs (9Aressy B. Ducommun B. Cell cycle control by the CDC25 phosphatases.Anticancer Agents Med. Chem. 2008; 8: 818-824Crossref PubMed Scopus (103) Google Scholar). Another unique feature of CDC25A distinguishing it from other isoforms is its rapid degradation in response to DNA damage or stalled replication forks. This mechanism is dependent on the ATM/ATR–CHK1/CHK2 pathway and is critical for the checkpoints that halt the cell cycle in response to genotoxic stresses (10Busino L. Chiesa M. Draetta G.F. Donzelli M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis.Oncogene. 2004; 23: 2050-2056Crossref PubMed Scopus (167) Google Scholar). Expression of CDC25A is periodically regulated during the cell cycle by both transcription and proteolysis. Transcription starting from late G1 is mediated by transcription factors including MYC and E2F (11Galaktionov K. X. D. phosphatase as a of PubMed Scopus Google H. et phosphatase is a of E2F and is for S Cell. Biol. PubMed Scopus Google A. J. E2F and of during cell cycle Cell. Biol. PubMed Scopus Google Scholar). CDC25C or is throughout the cell cycle M. Draetta G.F. mammalian checkpoints 2003; PubMed Scopus Google or is to degradation during mitosis V. M. Ducommun B. of human CDC25B phosphatase by A its Biol. Chem. PubMed Scopus Google CDC25A during mitosis in a A. M. J. J. of by Cdc25A of its J. PubMed Scopus Google Scholar). CDC25A is then to degradation by during mitotic and by during M. M. D. A. M. Draetta G.F. of degradation of A J. PubMed Scopus (167) Google Y. K. a in Cdc25A and Cdc25B A. 2005; PubMed Scopus (103) Google L. Donzelli M. Chiesa M. D. D. et of Cdc25A by during S phase and in response to DNA 2003; PubMed Scopus Google Scholar). DNA damage the degradation of CDC25A phosphorylation by J. M. J. et of human Cdc25A in response to DNA PubMed Scopus Google M. J. Draetta G.F. A in response to S phase and its in PubMed Scopus Google Scholar). to cyclin A at in the cell cycle. S phase, phosphorylation of of the complexes by cyclin complexes is involved in both the of DNA replication as as the of the same the same cell cycle control in the of DNA Biol. 2011; PubMed Scopus Google Scholar). Cyclin A during its is is that cyclin A is a of the engine that drives cells into is that cyclin A is of the that the activation of (2Fung T.K. Poon R.Y. A roller coaster ride with the mitotic cyclins.Semin. Cell Dev. Biol. 2005; 16: 335-342Crossref PubMed Scopus (142) Google A. Rodríguez-Bravo V. Medema R.H. The decision to enter mitosis: feedback and redundancy in the mitotic entry network.J. Cell Biol. 2009; 185: 193-202Crossref PubMed Scopus (431) Google Scholar). For example, cyclin in on then activates CDC25C to cyclin B–CDK1 activation L. D. B. J. activation in late G2 to PubMed Scopus Google L. L. A. et phosphorylation of is the mitotic Cell. PubMed Scopus Google Scholar). In this study, we uncovered an relationship between cyclin A and CDC25A. of cyclin A an accumulation of CDC25A an increase of provide evidence of a compensatory mechanism that timely entry into mitosis at levels of cyclin A. initially that of cyclin A in cells with promoted an accumulation of CDC25A was that depletion of cyclin A was not and cell cycle was not after This that the increase of CDC25A not complete depletion of cyclin A or in cell cycle the with including and we generated a conditional cell line for acute and silencing of cyclin A on a transcriptional system H.T. X. Poon R.Y.C. by transcriptional and Cycle. PubMed Scopus Google T.K. H.T. Poon R.Y.C. for of conditional silencing human cell Biol. Cell. 2021; PubMed Scopus Google Scholar). with the disruption of cyclin A with an of cyclin A was to the CRISPR-Cas9 to the of at the the control of a was into the Transcription of the by be using Moreover, cyclin A be to rapid was that cells lacking cyclin A and A as to A in response to and in a cyclin The A was to a as the cyclin A and was after the a that of A at at after The of A was with a rapid and accumulation of CDC25A In the of CDC25A at to the increase in DNA damage and after cyclin A depletion by the accumulation of and cyclin A in in both S and and As CDC25A before of cell cycle it is that the increase of CDC25A was an of cell cycle This was using cells the increase of CDC25A after cyclin A was using other of that it was not a of other CDK1T14/Y15 kinases and including and MYT1 by cyclin A depletion the cell line was a system by we a cyclin A into the cells before A. that A the accumulation of CDC25A. the of CDC25A was generally in control cells, of cyclin A was to CDC25A we generated in cells and that CDC25A was in the of cyclin A, that the was not to cells using a as we generated depletion of cell cyclin and in lacking the cell on the cells in S phase with a before with for to the proteins. By to cyclin A, depletion of cyclin or during S phase not in CDC25A accumulation a specific of cyclin A in this these results that depletion of cyclin A the rapid and specific accumulation of CDC25A. of the in cyclin A is to the of cyclin A during the cell cycle at both S phase and mitosis and binding to both CDK1 and Moreover, CDC25A is regulated during the cell cycle (10Busino L. Chiesa M. Draetta G.F. Donzelli M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis.Oncogene. 2004; 23: 2050-2056Crossref PubMed Scopus (167) Google Scholar). the that the accumulation of CDC25A by cyclin A depletion was caused by a disruption of the cell we the of cyclin A at different of the cell cycle using the cell cycle of CDC25A in cells As CDC25A was in early S phase and to in S and was during mitosis and in with its M. M. D. A. M. Draetta G.F. of degradation of A J. PubMed Scopus (167) Google Scholar). As both cyclin A and CDC25A in early it is not that cyclin A during that not CDC25A of cyclin A in late G1 was to an accumulation of CDC25A cells into S phase using a amount of CDC25A after cyclin A was is that CDC25A was cyclin A was in cells with that cell cycle was not for cyclin CDC25A This that cell cycle delay caused by cyclin A depletion was not for CDC25A In as cyclin A depletion delayed S and it is that CDC25A of as cell cycle caused by cyclin A depletion a in CDC25A cyclin A in G2 or mitotic cells promoted CDC25A Taken together, these data that the increase of CDC25A after cyclin A depletion throughout the cell cycle and is independent on cell cycle caused by cyclin A deficiency. A mechanism of CDC25A regulation during the cell cycle is be by J. M. J. et of human Cdc25A in response to DNA PubMed Scopus Google H. A. E.C. et Cdc25A degradation as a critical mechanism for normal cell cycle Cell Google Scholar). As J. L. et the S phase checkpoint by the and of Cell. 2003; PubMed Scopus Google of using a small CDC25A CDC25A was after cyclin A was that the increase of CDC25A cyclin A depletion was independent on the the CDC25A in cyclin A-depleted cells be to degradation after the DNA CDC25A degradation mechanism in the of cyclin A CDC25A was to a after of the presence or of cyclin A we other of and after cyclin A degradation D. M. by the and the of 2008; 8: PubMed Scopus Google Scholar). the of of WEE1 and or cyclin and was by cyclin A these data that the increase of CDC25A after cyclin A is not caused by or the protein stability of CDC25A by using to protein CDC25A was at a before the of in cyclin A-depleted cells in control cells, its protein stability was not after cyclin A was The of CDC25A in both cyclin and cells after the of In with the DNA damage the stability of CDC25A in both cyclin and that of the the of CDC25A by a was after the of cyclin A As a both and CDC25A be with a and This evidence that the regulation of CDC25A by cyclin A was not caused by a change in protein that the protein stability of CDC25A was not by cyclin A, we the of CDC25A was by cyclin A. that CDC25A after the of cyclin A in a results using an cell line that CDK2, a G2–M delay cells lacking cyclin A in using that CDC25A was after cyclin A was in cells By contrast, CDC25B and CDC25C in the of cyclin A. Taken together, these results that the increase in CDC25A after of cyclin A was mainly caused by an increase in transcriptional activity instead of a change in protein the of CDC25A accumulation in response to the of cyclin A, CDC25A was with and mitotic entry was at using the of the that CDC25A was to a to that before cyclin A was The cells into the cell cycle from a before the cyclin A As mitotic entry was after the of cyclin A. CDC25A delayed mitotic entry was delayed CDC25A was in cyclin A-depleted cells, that the normal accumulation of CDC25A in these cells was for for the of cyclin A. A delay in mitotic entry was after cyclin A and CDC25A in cells in late G2 using the CDK1 In to depletion of CDC25C not delay G2–M in the presence or of cyclin A In to the delay in the of mitosis was after of cyclin A and CDC25A The delay in G2–M in cyclin and cells was with an phosphorylation As was not the G2–M delay was to be caused by DNA damage with the Taken together, these data a mechanism in CDC25A is involved in the of cyclin A for timely entry into cyclin A and CDC25A to play critical in the cell evidence roles is generally For cyclin A, this is in to the presence of other cyclin–CDK pairs functioning at of the cell cycle (cyclin and cyclin for G2–M and as as the of cyclin A. the presence of CDC25B and CDC25C the of on in both G2–M and This is by the of CDKs from CDK1 are regulated by inhibitory phosphorylation in different cell For example, inhibitory phosphorylation a in the regulation of CDK1 a for during the cell cycle of cells H.T. Poon R.Y. of inhibitory phosphorylation of and for cell cycle control and DNA Biol. Chem. 2003; PubMed Scopus Google Scholar). with a of in S phase entry by J. J. for inhibitory phosphorylation during replication by a human A. PubMed Scopus Google Scholar). In this study, we that of cyclin A with or CRISPR-Cas9 combination with a conditional depletion and promoted the accumulation of CDC25A. of cyclin A CDC25A the increase of CDC25A was cyclin A was or before for A and CDC25A is cell cycle regulated of evidence that the cyclin regulation of CDC25A was not to cell cycle the of CDC25A accumulation was before of cell cycle was with CDC25A in cyclin cells in late and G2 Moreover, CDC25A was after cyclin A during a S phase as depletion of cyclin A delayed as by and it is that cyclin A depletion instead of CDC25A a cell cycle was of CDC25A regulation by cyclin–CDK complexes phosphatase activity and protein (10Busino L. Chiesa M. Draetta G.F. Donzelli M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis.Oncogene. 2004; 23: 2050-2056Crossref PubMed Scopus (167) Google Scholar). of and of CDC25A by cyclin B–CDK1 during mitosis CDC25A A. M. J. J. of by Cdc25A of its J. PubMed Scopus Google Scholar). of by cyclin–CDK at late its activity its stability L. A. A. et of CDC25A on in late by complexes mitotic Cycle. 15: PubMed Scopus Google Scholar). On the other cyclin complexes are in CDC25A by phosphorylating the phosphorylation of for degradation L. 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Chem. 2004; PubMed Scopus Google J. J. et phosphorylation of the transcription and its in the Biol. Chem. 2003; PubMed Scopus Google J. M. M. L. et of during G2 cyclin of by the Cell. Biol. 2008; PubMed Scopus Google J. is and directly by and CDK1 in Cell 2014; 2: PubMed Scopus Google and the pathway Cyclin-dependent kinase the of with Res. 2004; PubMed Scopus Google H. L. V. B. Cyclin mitotic Biol. Chem. 2009; PubMed Scopus Google et of by cyclin-dependent kinase Biol. Chem. 2004; PubMed Scopus Google Scholar). In it is that the of in the that regulate CDC25A may be regulated by cyclin A. Cyclin A the of the CDC25A of evidence that CDC25A is the of the CDC25 is evidence that CDC25B is an of G2–M its activation of the of cyclin is then to the autocatalytic loop to all the cyclin B–CDK1 Cell cycle regulation by the phosphatase Cell Res. PubMed Scopus Google Scholar). Cdc25B and Cdc25C are not for (8Ferguson A.M. White L.S. Donovan P.J. Piwnica-Worms H. Normal cell cycle and checkpoint responses in mice and cells lacking Cdc25B and Cdc25C protein phosphatases.Mol. Cell. Biol. 2005; 25: 2853-2860Crossref PubMed Scopus (124) Google Scholar). a with of CDC25B in human not of including and T.K. et CDC25B is a for a with and PubMed Scopus Google Scholar). On the other Cdc25A is essential for (7Ray D. Terao Y. Nimbalkar D. Hirai H. Osmundson E.C. Zou X. et al.Hemizygous disruption of Cdc25A inhibits cellular transformation and mammary tumorigenesis in mice.Cancer Res. 2007; 67: 6605-6611Crossref PubMed Scopus (68) Google Scholar). to cyclin A, CDC25A to play roles in both the G1–S and G2–M (9Aressy B. Ducommun B. Cell cycle control by the CDC25 phosphatases.Anticancer Agents Med. Chem. 2008; 8: 818-824Crossref PubMed Scopus (103) Google Scholar). data that CDC25A is in a to for the of cyclin A during the cell cycle. cyclin A and CDC25A at levels in the cell cycle during it is not that depletion of cyclin A the increase in during G1 not the of S phase entry that cyclin A is an of the S its is to In with this are generated after the of cyclin A J. Cyclin DNA and to DNA and in human 8: PubMed Scopus Google Scholar). is evidence that of CDC25A by replication and M. genotoxic by mitotic of replication Cell Biol. PubMed Scopus Google Scholar). The DNA are then into M. A. et of cyclin or Cdc25A to replication mitotic and to replication checkpoint PubMed Scopus Google Scholar). of CDC25A in human V. Ducommun B. CDC25 in 2007; PubMed Scopus Google Scholar). CDC25A with or of in transformation K. J. Draetta J. M. et as human PubMed Scopus Google D. Terao Y. K. et CDC25A mammary tumorigenesis with Res. 2007; 67: PubMed Scopus Google Scholar). of cyclin A and the CDC25A accumulation are to in that cyclin A is an increase of CDC25A the CDK activities by activating cyclin cyclin A be by a of CDC25A to delay mitotic This mechanism may that mitotic entry be to at an in of different of cyclin A for a In of this that both cyclin A and CDC25A for G2–M in cells Moreover, mitotic entry was delayed in cyclin cells by CDC25A to a to before cyclin A was As CDC25A is to play a critical in the DNA damage checkpoints (10Busino L. Chiesa M. Draetta G.F. Donzelli M. Cdc25A phosphatase: combinatorial phosphorylation, ubiquitylation and proteolysis.Oncogene. 2004; 23: 2050-2056Crossref PubMed Scopus (167) Google that cyclin A may to is the of this as CDC25A be after in cyclin cells it is that with cyclin A was by the of CDC25A on the DNA damage results that transcription regulation of CDC25A by cyclin A may a of CDC25 for mitotic This is with other activation of CDC25A including activation of phosphatase activation as as as of the protein. CRISPR-Cas9 cyclin A or CDC25A by the of and or and to from from CRISPR-Cas9 in was generated as H.T. X. Poon R.Y.C. by transcriptional and Cycle. PubMed Scopus Google Scholar). A in was generated as T.K. Poon R.Y. The of cyclin A and Cycle. 2005; PubMed Scopus Google Scholar). into cyclin A with a In the A in T.K. A. Poon R.Y. Cyclin is during by different from other Biol. Chem. PubMed Scopus Google was as a and with and and and then in the using the and A generated by of the into H.T. X. 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PubMed Scopus Google Scholar). was with a from a cell and into an system with and control for to was with and was using of of the cells was and to be after was as H.T. Poon R.Y.C. between and DNA damage and the G2 DNA damage PubMed Scopus Google Scholar). cells and with The cells then with and with a and A at for DNA of cells with For cells with of for before The cells then with at for the was with before with at for with the the cells with at for The cell after with and with with and The cell was in and with of at for The cells then with before with of at for in the with the cells to and transcription and as H.T. X. Poon R.Y.C. by transcriptional and Cycle. PubMed Scopus Google Scholar). 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