Cancer is a group of diseases in which cells continue to multiply in an unregulated manner. The main regulation of initiation of a new cell division cycle is imposed during a specific phase of the cell cycle called G1. Proteins that control exit from G1-phase, including those involved in regulating G1-S transcription, are often found mutated in human tumour cells, suggesting that inactivation of this pathway may be necessary for tumour development.
Once a cell commits to a new cell division cycle the DNA structure checkpoints can restrict cell-cycle progression in response to the detection of abnormalities in the genetic material in order to repair the detected damage. When these checkpoints fail, cells are at risk of increased genetic abnormalities, phenomena that are associated with tumour development. Part of the checkpoint control includes regulation of the cell cycle transcriptional program. However, it was not understood how checkpoints act on the cell cycle transcription program, nor has the functional significance of this control been rigorously tested in any experimental system.
We recently identified the novel transcriptional repressor Nrm1 as a key regulator in turning off G1-S transcription during exit from the G1 phase of the cell cycle in both budding Saccharomyces cerevisiae and fission yeast Schizosaccharomyces pombe . We established that Nrm1, which performs an analogous function to the mammalian pocket proteins, is a target of the DNA replication checkpoint pathway. This suggests that it is at the nexus between the cell-cycle transcriptional program and the DNA replication checkpoint.
This presents a unique opportunity to achieve an unprecedented level of understanding about the relationship between cell-cycle regulated transcription and control of genome integrity. The degree of conservation from yeast to human of both the G1-S transcription network and the DNA replication checkpoint response suggest that regulation of G1-S transcription by the DNA replication checkpoint may also be conserved in mammals. Our latest work does indicate that regulation of G1-S transcription by the DNA replication checkpoint is conserved in human cells. The opportunity to study this regulation in both yeasts promises to reveal conserved aspects of its function that will guide our future research into human biology and disease. In that context, our main aim is to investigate the spectrum of activities, resulting from regulating G1-S genes by the DNA structure checkpoints that can contribute to recovery from genotoxic stress in eukaryotes.
|Bertoli, C; De Bruin, RAM; (2014) Turning cell cycle entry on its head: New data on the relationship between two proteins, cyclin d and rb, suggest that we need to re-evaluate our understanding of how cells enter into the cell cycle. eLife , 2014 (3) 10.7554/eLife.03475. |
|Caetano, C; Limbo, O; Farmer, S; Klier, S; Dovey, C; Russell, P; de Bruin, RA; (2014) Tolerance of Deregulated G1/S Transcription Depends on Critical G1/S Regulon Genes to Prevent Catastrophic Genome Instability. Cell Rep 10.1016/j.celrep.2014.11.039. |
|Klier, S; Farmer, S; de Bruin, RA; (2014) Analyzing G1-S transcriptional control. Methods Mol Biol , 1170 463 - 476. 10.1007/978-1-4939-0888-2_25. |
|Bertoli, C; Klier, S; McGowan, C; Wittenberg, C; de Bruin, RA; (2013) Chk1 inhibits E2F6 repressor function in response to replication stress to maintain cell-cycle transcription. Curr Biol , 23 (17) 1629 - 1637. 10.1016/j.cub.2013.06.063. |
|Bertoli, C; Skotheim, JM; de Bruin, RA; (2013) Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol , 14 (8) 518 - 528. 10.1038/nrm3629. |
|Harris, MR; Lee, D; Farmer, S; Lowndes, NF; de Bruin, RA; (2013) Binding specificity of the G1/S transcriptional regulators in budding yeast. PLoS One , 8 (4) , Article e61059. 10.1371/journal.pone.0061059. |
|Travesa, A; Kalashnikova, TI; de Bruin, RA; Cass, SR; Chahwan, C; Lee, DE; ... Wittenberg, C; + view all Travesa, A; Kalashnikova, TI; de Bruin, RA; Cass, SR; Chahwan, C; Lee, DE; Lowndes, NF; Wittenberg, C; - view fewer (2013) Repression of G1/S transcription is mediated via interaction of the GTB motifs of Nrm1 and Whi5 with Swi6. Mol Cell Biol , 33 (8) 1476 - 1486. 10.1128/MCB.01333-12. |
|Bastos de Oliveira, FM; Harris, MR; Brazauskas, P; de Bruin, RA; Smolka, MB; (2012) Linking DNA replication checkpoint to MBF cell-cycle transcription reveals a distinct class of G1/S genes. EMBO J , 31 (7) 1798 - 1810. 10.1038/emboj.2012.27. |
|Smolka, MB; Bastos de Oliveira, FM; Harris, MR; de Bruin, RA; (2012) The checkpoint transcriptional response: make sure to turn it off once you are satisfied. Cell Cycle , 11 (17) 3166 - 3174. 10.4161/cc.21197. |
|Travesa, A; Kuo, D; de Bruin, RA; Kalashnikova, TI; Guaderrama, M; Thai, K; ... Wittenberg, C; + view all Travesa, A; Kuo, D; de Bruin, RA; Kalashnikova, TI; Guaderrama, M; Thai, K; Aslanian, A; Smolka, MB; Yates, JR; Ideker, T; Wittenberg, C; - view fewer (2012) DNA replication stress differentially regulates G1/S genes via Rad53-dependent inactivation of Nrm1. EMBO J , 31 (7) 1811 - 1822. 10.1038/emboj.2012.28. |
|Caetano, C; Klier, S; de Bruin, RAM; (2011) Phosphorylation of the MBF Repressor Yox1p by the DNA Replication Checkpoint Keeps the G1/S Cell-Cycle Transcriptional Program Active. PLOS ONE , 6 (2) , Article e17211. 10.1371/journal.pone.0017211. |
|Aligianni, S; Lackner, DH; Klier, S; Rustici, G; Wilhelm, BT; Marguerat, S; ... Bahler, J; + view all Aligianni, S; Lackner, DH; Klier, S; Rustici, G; Wilhelm, BT; Marguerat, S; Codlin, S; Brazma, A; de Bruin, RAM; Bahler, J; - view fewer (2009) The Fission Yeast Homeodomain Protein Yox1p Binds to MBF and Confines MBF-Dependent Cell-Cycle Transcription to G1-S via Negative Feedback. PLoS Genetics , 5 (8) , Article e1000626. 10.1371/journal.pgen.1000626. |
|de Bruin, RAM; Wittenberg, C; (2009) All eukaryotes: Before turning off G(1)-S transcription, please check your DNA. CELL CYCLE , 8 (2) 214 - 217. |
|Wagner, MV; Smolka, MB; de Bruin, RAM; Zhou, HL; Wittenberg, C; Dowdy, SF; (2009) Whi5 Regulation by Site Specific CDK-Phosphorylation in Saccharomyces cerevisiae. PLOS ONE , 4 (1) , Article e4300. 10.1371/journal.pone.0004300. |
|Ashe, M; de Bruin, RAM; Kalashnikova, T; McDonald, WH; Yates, JR; Wittenberg, C; (2008) The SBF- and MBF-associated protein Msa1 is required for proper timing of G(1)-specific transcription in Saccharomyces cerevisiae. J BIOL CHEM , 283 (10) 6040 - 6049. 10.1074/jbc.M708248200. |
|de Bruin, RAM; Kalashnikova, TI; Aslanian, A; Wohischlegel, J; Chahwan, C; Yates, JR; ... Wittenberg, C; + view all de Bruin, RAM; Kalashnikova, TI; Aslanian, A; Wohischlegel, J; Chahwan, C; Yates, JR; Russell, P; Wittenberg, C; - view fewer (2008) DNA replication checkpoint promotes G(1)-S transcription by inactivating the MBF repressor Nrm1. P NATL ACAD SCI USA , 105 (32) 11230 - 11235. 10.1073/pnas.0801106105. |
|de Bruin, RAM; Kalashnikova, TI; Wittenberg, C; (2008) Stb1 Collaborates with Other Regulators To Modulate the G(1)-Specific Transcriptional Circuit. MOL CELL BIOL , 28 (22) 6919 - 6928. 10.1128/MCB.00211-08. |
|Souer, E; Rebocho, AB; Bliek, M; Kusters, E; de Bruin, RAM; Koes, R; (2008) Patterning of inflorescences and flowers by the F-box protein DOUBLE TOP and the LEAFY homolog ABERRANT LEAF AND FLOWER of petunia. PLANT CELL , 20 (8) 2033 - 2048. 10.1105/tpc.108.060871. |
|Limbo, O; Chahwan, C; Yamada, Y; de Bruin, RAM; Wittenberg, C; Russell, P; (2007) Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. MOL CELL , 28 (1) 134 - 146. 10.1016/j.molcel.2007.09.009. |
|de Bruin, RAM; Kalashnikova, TI; Chahwan, C; McDonald, WH; Wohlschlegel, J; Yates, J; ... Wittenberg, C; + view all de Bruin, RAM; Kalashnikova, TI; Chahwan, C; McDonald, WH; Wohlschlegel, J; Yates, J; Russell, P; Wittenberg, C; - view fewer (2006) Constraining G1-specific transcription to late G1 phase: The MBF-associated corepressor Nrm1 acts via negative feedback. MOL CELL , 23 (4) 483 - 496. 10.1016/j.molcel.2006.06.025. |
|de Bruin, RAM; McDonald, WH; Kalashnikova, TI; Yates, J; Wittenberg, C; (2004) Cln3 activates G1-specific transcription via phosphorylation of the SBF transcription bound repressor Whi5. CELL , 117 (7) 887 - 898. |
|Johnsson, A; Byrne, P; de Bruin, R; Weiner, D; Wong, J; Los, G; (2001) Identification of gene clusters differentially expressed during the cellular injury responses (CIR) to cisplatin. Br J Cancer , 85 (8) 1206 - 1210. 10.1054/bjoc.2001.2080. |
|Stam, M; de Bruin, R; van Blokland, R; van der Hoorn, RA; Mol, JN; Kooter, JM; (2000) Distinct features of post-transcriptional gene silencing by antisense transgenes in single copy and inverted T-DNA repeat loci. Plant J , 21 (1) 27 - 42. |
|de Bruin, R; Spelt, K; Mol, J; Koes, R; Quattrocchio, F; (1999) Selection of high-affinity phage antibodies from phage display libraries. Nat Biotechnol , 17 (4) 397 - 399. 10.1038/7959. |
|de las Alas, MM; de Bruin, RAM; Ten Eyck, L; Los, G; Howell, SB; (1998) Generating a theoretical model of the DNA mismatch repair protein hMSH2 using prediction-based threading. J MOL GRAPH MODEL , 16 (4-6) 286 - 286. |
|De Las Alas, MM; De Bruin, RAM; Ten Eyck, L; Los, G; Howell, SB; (1998) Prediction-based threading of the hMSH2 DNA mismatch repair protein. FASEB J , 12 (9) 653 - 663. |
|Stam, M; De Bruin, R; Kenter, S; Van der Hoorn, RAL; Van Blokland, R; Mol, JNM; Kooter, JM; (1997) Post-transcriptional silencing of chalcone synthase in petunia by inverted transgene repeats. Plant Journal , 12 (1) 63 - 82. |