The P53-p21-DREAM-CDE/CHR Pathway Regulates G2/M Cell Cycle Genes

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2015 Sep 20

PMID 26384566

Citations 176

Authors

Martin Fischer

Marianne Quaas

Lydia Steiner

Kurt Engeland

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor p53 functions predominantly as a transcription factor by activating and downregulating gene expression, leading to cell cycle arrest or apoptosis. p53 was shown to indirectly repress transcription of the CCNB2, KIF23 and PLK4 cell cycle genes through the recently discovered p53-p21-DREAM-CDE/CHR pathway. However, it remained unclear whether this pathway is commonly used. Here, we identify genes regulated by p53 through this pathway in a genome-wide computational approach. The bioinformatic analysis is based on genome-wide DREAM complex binding data, p53-depedent mRNA expression data and a genome-wide definition of phylogenetically conserved CHR promoter elements. We find 210 target genes that are expected to be regulated by the p53-p21-DREAM-CDE/CHR pathway. The target gene list was verified by detailed analysis of p53-dependent repression of the cell cycle genes B-MYB (MYBL2), BUB1, CCNA2, CCNB1, CHEK2, MELK, POLD1, RAD18 and RAD54L. Most of the 210 target genes are essential regulators of G2 phase and mitosis. Thus, downregulation of these genes through the p53-p21-DREAM-CDE/CHR pathway appears to be a principal mechanism for G2/M cell cycle arrest by p53.

Citing Articles

Novel Camptothecin Derivative 9c with Enhanced Antitumor Activity via NSA2-EGFR-P53 Signaling Pathway.

Du F, Zhang A, Qi X, Yin R, Jiang T, Li J Int J Mol Sci. 2025; 26(5).

PMID: 40076615 PMC: 11900506. DOI: 10.3390/ijms26051987.

CeDaD-a novel assay for simultaneous tracking of cell death and division in a single population.

Noltner L, Engeland K, Kohler R Cell Death Discov. 2025; 11(1):86.

PMID: 40038265 PMC: 11880512. DOI: 10.1038/s41420-025-02370-7.

MOGAN for LUAD Subtype Classification by Integrating Three Omics Data Types.

He H, Wang L, Ma M Cancer Innov. 2025; 4(2):e160.

PMID: 40026873 PMC: 11868734. DOI: 10.1002/cai2.160.

Thymidine kinase 1 indicates resistance to immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.

Wang J, Xu X, Wang Y, Zhu Y Cell Oncol (Dordr). 2025; .

PMID: 40009128 DOI: 10.1007/s13402-025-01048-7.

Prognosis and immune infiltration prediction in neuroblastoma based on neutrophil extracellular traps-related gene signature.

Aierken Y, Tan K, Liu T, Lv Z Sci Rep. 2025; 15(1):5343.

PMID: 39948114 PMC: 11825912. DOI: 10.1038/s41598-025-88608-x.

References

Fischer M, Grundke I, Sohr S, Quaas M, Hoffmann S, Knorck A . p53 and cell cycle dependent transcription of kinesin family member 23 (KIF23) is controlled via a CHR promoter element bound by DREAM and MMB complexes. PLoS One. 2013; 8(5):e63187. PMC: 3641139. DOI: 10.1371/journal.pone.0063187. View

Sadasivam S, DeCaprio J . The DREAM complex: master coordinator of cell cycle-dependent gene expression. Nat Rev Cancer. 2013; 13(8):585-95. PMC: 3986830. DOI: 10.1038/nrc3556. View

Schlereth K, Heyl C, Krampitz A, Mernberger M, Finkernagel F, Scharfe M . Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions. PLoS Genet. 2013; 9(8):e1003726. PMC: 3744428. DOI: 10.1371/journal.pgen.1003726. View

Menendez D, Nguyen T, Freudenberg J, Mathew V, Anderson C, Jothi R . Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells. Nucleic Acids Res. 2013; 41(15):7286-301. PMC: 3753631. DOI: 10.1093/nar/gkt504. View

Fischer M, Quaas M, Wintsche A, Muller G, Engeland K . Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein. Nucleic Acids Res. 2013; 42(1):163-80. PMC: 3874167. DOI: 10.1093/nar/gkt849. View

Benson E, Mungamuri S, Attie O, Kracikova M, Sachidanandam R, Manfredi J . p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes. Oncogene. 2013; 33(30):3959-69. PMC: 4067464. DOI: 10.1038/onc.2013.378. View

Muller G, Wintsche A, Stangner K, Prohaska S, Stadler P, Engeland K . The CHR site: definition and genome-wide identification of a cell cycle transcriptional element. Nucleic Acids Res. 2014; 42(16):10331-50. PMC: 4176359. DOI: 10.1093/nar/gku696. View

Fischer M, Steiner L, Engeland K . The transcription factor p53: not a repressor, solely an activator. Cell Cycle. 2014; 13(19):3037-58. PMC: 4612452. DOI: 10.4161/15384101.2014.949083. View

Klein D, Hoffmann S, Ahlskog J, OHanlon K, Quaas M, Larsen B . Cyclin F suppresses B-Myb activity to promote cell cycle checkpoint control. Nat Commun. 2015; 6:5800. DOI: 10.1038/ncomms6800. View

10.

Chang B, Watanabe K, Broude E, Fang J, Poole J, Kalinichenko T . Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A. 2000; 97(8):4291-6. PMC: 18232. DOI: 10.1073/pnas.97.8.4291. View

11.

Flatt P, Tang L, Scatena C, Szak S, Pietenpol J . p53 regulation of G(2) checkpoint is retinoblastoma protein dependent. Mol Cell Biol. 2000; 20(12):4210-23. PMC: 85790. DOI: 10.1128/MCB.20.12.4210-4223.2000. View

12.

Gottifredi V, Karni-Schmidt O, Shieh S, Prives C . p53 down-regulates CHK1 through p21 and the retinoblastoma protein. Mol Cell Biol. 2001; 21(4):1066-76. PMC: 99561. DOI: 10.1128/MCB.21.4.1066-1076.2001. View

13.

Li B, Lee M . Transcriptional regulation of the human DNA polymerase delta catalytic subunit gene POLD1 by p53 tumor suppressor and Sp1. J Biol Chem. 2001; 276(32):29729-39. DOI: 10.1074/jbc.M101167200. View

14.

Zhu H, Chang B, Uchiumi T, Roninson I . Identification of promoter elements responsible for transcriptional inhibition of polo-like kinase 1 and topoisomerase IIalpha genes by p21(WAF1/CIP1/SDI1). Cell Cycle. 2002; 1(1):59-66. View

15.

Wasner M, Tschop K, Spiesbach K, Haugwitz U, Johne C, Mossner J . Cyclin B1 transcription is enhanced by the p300 coactivator and regulated during the cell cycle by a CHR-dependent repression mechanism. FEBS Lett. 2003; 536(1-3):66-70. DOI: 10.1016/s0014-5793(03)00028-0. View

16.

Mirza A, Wu Q, Wang L, McClanahan T, Bishop W, Gheyas F . Global transcriptional program of p53 target genes during the process of apoptosis and cell cycle progression. Oncogene. 2003; 22(23):3645-54. DOI: 10.1038/sj.onc.1206477. View

17.

Lohr K, Moritz C, Contente A, Dobbelstein M . p21/CDKN1A mediates negative regulation of transcription by p53. J Biol Chem. 2003; 278(35):32507-16. DOI: 10.1074/jbc.M212517200. View

18.

Vousden K, Prives C . Blinded by the Light: The Growing Complexity of p53. Cell. 2009; 137(3):413-31. DOI: 10.1016/j.cell.2009.04.037. View

19.

Banerjee T, Nath S, Roychoudhury S . DNA damage induced p53 downregulates Cdc20 by direct binding to its promoter causing chromatin remodeling. Nucleic Acids Res. 2009; 37(8):2688-98. PMC: 2677870. DOI: 10.1093/nar/gkp110. View

20.

Zwicker J, Lucibello F, Wolfraim L, Gross C, Truss M, Engeland K . Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression. EMBO J. 1995; 14(18):4514-22. PMC: 394543. DOI: 10.1002/j.1460-2075.1995.tb00130.x. View