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J. Biol. Chem., Vol. 278, Issue 17, 14985-14995, April 25, 2003
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§,§,
From the 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 knockdown of DNMT1
(DNA methyltransferase 1) 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-aza-2'-deoxycytidine, 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 suggest that the intra-S-phase
arrest is triggered by a reduction in DNMT1 and not by demethylation of
DNA. DNMT1 knockdown also leads to an induction of a set of genes that
are implicated in genotoxic stress response such as
NF- Department of Pharmacology and Therapeutics,
McGill University, Montreal, Quebec H3G 1Y6, Canada and
¶ Laboratoire de Virologie Moléculaire et Structurale, EA
2939, Faculté de Médecine et Pharmacie, Université
Joseph Fourier de Grenoble, Domaine de La Merci, Ave.
Gresivaudan, La Tronche 38706, France
B, JunB, ATF-3,
and GADD45
(growth arrest
DNA damage 45 gene). Based on
these data, we suggest that this stress response mechanism evolved to
guard against buildup of DNA methylation errors and to coordinate
inheritance of genomic and epigenomic information.
To whom correspondence should be addressed: Dept. of
Pharmacology and Therapeutics, McGill University, 3655 Sir William
Osler Promenade, Montreal, Quebec H3G 1Y6, Canada. Tel.:
514-398-7107; Fax: 514-398-6690.
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