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- W2186760915 abstract "Methylation ofcytosine residues inDNA plays animportant role inregulating geneexpression during vertebrate embryonic development. Conversely, disruption of normalpatterns ofmethylation iscommonintumors and occurs early inprogression ofsomehumancancers. Inver- tebrates, itappears thatthesameDNA methyltransferase maintains preexisting patterns ofmethylation during DNA replication andcarries outdenovomethylation tocreate new methylation patterns. Thereareseveral indications thatin- herent signals inDNAstructure canactinvivo toinitiate or blockde novomethylation inadjacent DNAregions. Toidentify sequences capable ofenhancing denovomethylation ofDNAin vitro, wedesigned aseries ofoligodeoxyribonucleotide sub- strates withsubstrate cytosine residues indifferent sequence contexts. We obtained evidence thatsome5-methylcytosine residues inthese single-stranded DNAscanstimulate denovo methylation ofadjacent sites bymurineDNA 5-cytosine methyltransferase aseffectively as5-methylcytosine residues indouble-stranded DNAstimulate maintenance methylation. Thissuggests thatdouble-stranded DNA maynotbethe primary natural substrate fordenovomethylation andthat looped single-stranded structures formed during thenormal course ofDNAreplication orrepair serve asnucleation sites fordenovomethylation ofadjacent DNAregions. Invertebrate cells, -3%ofcytosine (C)residues inDNA have amethyl grouponcarbon 5,and5-methylcytosine (5MeC) is theonlynaturally occurring modified basedetected inDNA (1). Enzymatic methylation ofC residues inDNA occurs postreplicatively andprimarily involves C residues inCpG dinucleotides, although methylation hasbeenobserved atC residues 5'ofother nucleotides (2). Theextent andpattern of methylation ofgenomic DNA isspecies- andtissue-specific (3), whichimplies thatthepattern ofmethylation isfaithfully inherited inallcells ofcommonlineage within a tissue. Analysis ofmethylation patterns ofspecific genesduring development suggests that patterns established inspermand oocytes arelost during early development, that regions other thanCpGislands becomealmost fully methylated, andthat loss ofmethylation occurs atspecific sites intissues wherea geneisexpressed (4-6). Although notallgenesareregulated bymethylation, hy- pomethylation atspecific sites orinspecific regions ina numberofgenes iscorrelated withactive transcription (7-9). DNAmethylation invitro canprevent efficient transcription of genes incell-free systems ortransient expression oftransfected genes; methylation ofCresidues insomespecific cis-regulatory regions canalsoblock orenhance binding oftranscription factors orrepressors (7-11). DNA methylation isinvolved in inactivation ofoneofthetwoX chromosomes infemale mammalian somatic cells (12), andallele-specific methylation hasbeenproposed asafactor ingenomic imprinting (13). The mostdirect evidence fortheimportance ofDNA methylation indevelopment isthedemonstration that homozygous muta- tioninmurineDNA 5-cytosine methyltransferase (5-C- MTase)leads toimpaired embryonic development (14). Conversely, disruption ofnormal patterns ofDNA methyl- ation hasbeenlinked todevelopment ofcancer. The5MeC content ofDNA fromtumors andtumor-derived cell lines is generally lower thaninnormal tissues (15), although increased methylation ofCpGsites occurs insomegenes andchromo- someregions (16). Whiletheseobservations support the concept that methylation patterns areestablished intheem- bryoandaltered during carcinogenesis byacombination ofde novomethylation andloss ofmethylation inatime-, sequence-, andtissue-specific manner, themechanism(s) bywhich these changes occur andareregulated withsuchapparent precision hasnotbeendefined. Theprocesses involved inregulating denovomethylation are particularly puzzling. Aswouldbepredicted foranenzyme thatmaintains established patterns ofmethylation during DNA replication, mammalian DNA MTaseshaveamuch greater capacity formethylating hemimethylated CpGsites in double-stranded (ds) DNA thancompletely unmethylated sites. However, since thegeneencoding mammalian DNA 5-C-MTase ispresent asasingle copyperhaploid genome(17) andthere isnodirect evidence fortheexistence ofaseparate denovoDNA MTase, itappears that thesameenzymemust carry outbothfunctions. Onthebasis ofprevious reports thatsingle-stranded (ss) oligodeoxyribonucleotides (ODNs)havewidely differing ca- pacities toserveassubstrates formurine DNA 5-C-MTase (18), wedesigned aseries of24-nt-long ODNswithmultiple CpGsites flanked byrestriction endonuclease cleavage sites to allow analysis oftheextent ofmethylation ateachsite. Here, wedescribe theeffect ofreplacement ofspecific C residues withSMeContherateofmethylation ofCpGsites inthese ODNsandpresent evidence thatsome5MeCresidues in ssDNAcandirect methylation ofCpGsites incis(onthesame strand)." @default.
- W2186760915 created "2016-06-24" @default.
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- W2186760915 date "1995-01-01" @default.
- W2186760915 modified "2023-09-27" @default.
- W2186760915 title "5-Methyl-2'-deoxycytidine insingle-stranded DNA canactincisto signal denovoDNA methylation" @default.
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- W2186760915 hasPublicationYear "1995" @default.
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