| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Papers In Press, published online ahead of print February 7, 2003
Pharmacology Dept., McGill University, Montreal, Quebec H3G 1Y6
Corresponding Author: mszyf{at}pharma.mcgill.ca
The DNA methylation pattern is an important component of the epigenome that regulates and maintains gene expression programs. In this paper we test the hypothesis that vertebrate cells possess mechanisms protecting them from epigenomic stress similar to DNA damage checkpoints. We show that knock down of DNA methyltransferase1 (DNMT1) by an antisense oligonucleotide triggers an intra-S-phase arrest of DNA replication that is not observed with control oligonucleotide. The cells are arrested at different positions throughout the S-phase of the cell cycle suggesting that this response is not specific to distinct classes of origins of replication. The intra S phase arrest of DNA replication is proposed to protect the genome from extensive DNA demethylation that could come about by replication in the absence of DNMT1. This protective mechanism is not induced by 5-azadeoxycytidine (5-aza-CdR) a nucleoside analog that inhibits DNA methylation by trapping DNMT1 in the progressing replication fork, but does not reduce de novo synthesis of DNMT1. Our data therefore suggests that the intra-S-phase arrest is triggered by a reduction in DNMT1 and not by demethylation of DNA. DNMT1 knock down also leads to an induction of a set of genes that are implicated in genotoxic stress response such as NF-kB, JUN-B, ATF3 and GADD45?. Based on this data we suggest that this stress response mechanism evolved to guard against build up of DNA methylation errors and to coordinate inheritance of genomic and epigenomic information.
J. Biol. Chem, 10.1074/jbc.M213219200
Submitted on December 27, 2002
Revised on February 5, 2003
Accepted on February 7, 2003
Epigenomic stress response: Knock-down of DNA methyltransferase 1 triggers an intra S-phase arrest of DNA replication and induction of stress response genes
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Milutinovic, A. C. D'Alessio, N. Detich, and M. Szyf Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes Carcinogenesis, March 1, 2007; 28(3): 560 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Torrisani, A. Unterberger, S. R. Tendulkar, K. Shikimi, and M. Szyf AUF1 Cell Cycle Variations Define Genomic DNA Methylation by Regulation of DNMT1 mRNA Stability Mol. Cell. Biol., January 1, 2007; 27(1): 395 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Unterberger, S. D. Andrews, I. C. G. Weaver, and M. Szyf DNA methyltransferase 1 knockdown activates a replication stress checkpoint. Mol. Cell. Biol., October 1, 2006; 26(20): 7575 - 7586. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Maatouk, L. D. Kellam, M. R. W. Mann, H. Lei, E. Li, M. S. Bartolomei, and J. L. Resnick DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages Development, September 1, 2006; 133(17): 3411 - 3418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Loriot, E. De Plaen, T. Boon, and C. De Smet Transient Down-regulation of DNMT1 Methyltransferase Leads to Activation and Stable Hypomethylation of MAGE-A1 in Melanoma Cells J. Biol. Chem., April 14, 2006; 281(15): 10118 - 10126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Kassis, M. Zhao, J. A. Hong, G. A. Chen, D. M. Nguyen, and D. S. Schrump Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells J. Thorac. Cardiovasc. Surg., February 1, 2006; 131(2): 298 - 306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Ting, K.-w. Jair, K. E. Schuebel, and S. B. Baylin Differential Requirement for DNA Methyltransferase 1 in Maintaining Human Cancer Cell Gene Promoter Hypermethylation Cancer Res., January 15, 2006; 66(2): 729 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Carlone, J.-H. Lee, S. R. L. Young, E. Dobrota, J. S. Butler, J. Ruiz, and D. G. Skalnik Reduced Genomic Cytosine Methylation and Defective Cellular Differentiation in Embryonic Stem Cells Lacking CpG Binding Protein Mol. Cell. Biol., June 15, 2005; 25(12): 4881 - 4891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Milutinovic, S. E. Brown, Q. Zhuang, and M. Szyf DNA Methyltransferase 1 Knock Down Induces Gene Expression by a Mechanism Independent of DNA Methylation and Histone Deacetylation J. Biol. Chem., July 2, 2004; 279(27): 27915 - 27927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Campbell, V. Bovenzi, and M. Szyf Methylated DNA-binding protein 2 antisense inhibitors suppress tumourigenesis of human cancer cell lines in vitro and in vivo Carcinogenesis, April 1, 2004; 25(4): 499 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Cheng, D. J. Weisenberger, F. A. Gonzales, G. Liang, G.-L. Xu, Y.-G. Hu, V. E. Marquez, and P. A. Jones Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells Mol. Cell. Biol., February 1, 2004; 24(3): 1270 - 1278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matsukura, P. A. Jones, and D. Takai Establishment of conditional vectors for hairpin siRNA knockdowns Nucleic Acids Res., August 1, 2003; 31(15): e77 - e77. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
