A conserved 3′-untranslated element mediates growth regulation of DNA methyltransferase 1 and inhibits its transforming activity

被引:41
作者
Detich, N [1 ]
Ramchandani, S [1 ]
Szyf, M [1 ]
机构
[1] McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ H3G 1Y6, Canada
关键词
D O I
10.1074/jbc.M103056200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ectopic expression of DNA methyltransferase 1 (DNMT1) has been proposed to play an important role in cancer. dnmt1 mRNA is undetectable in growth-arrested cells but is induced upon entrance into the S phase of the cell cycle, and until now, the mechanisms responsible for this regulation were unknown. In this report, we demonstrate that the 3 ' -untranslated region (3 ' -UTR) of the dnmt1 mRNA can confer a growth-dependent regulation on its own message as well as a heterologous beta -globin mRNA Our results indicate that a 54-nucleotide highly conserved element within the 3 ' -UTR is necessary and sufficient to mediate this regulation. Cell-free mRNA decay experiments demonstrate that this element increases mRNA turnover rates and does so to a greater extent in the presence of extracts prepared from arrested cells. A specific RNA-protein complex is formed with the 3 ' -UTR only in growth-arrested cells, and a UV cross-linking analysis revealed a 40-kDa protein (p40), the binding of which is dramatically increased in growth-arrested cells and is inversely correlated with dnmt1 mRNA levels as cells are induced into the cell cycle. Although ectopic expression of human DNMT1 lacking the 3 ' -UTR can transform NIH-3T3 cells, inclusion of the 3 ' -UTR prevents transformation. These results support the hypothesis that deregulated expression of DNMT1 with the cell cycle is important for cellular transformation.
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页码:24881 / 24890
页数:10
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