Inhibition of poly(ADP-ribosyl)ation induces DNA hypermethylation: a possible molecular mechanism.
The pattern of DNA methylation established during embryonic development is necessary for the control of gene expression and is preserved during the replicative process. DNA regions of about 1-2 kb in size, termed CpG islands and located mostly in the promoter regions of housekeeping genes, are protected from methylation, despite being about 6-10 times richer in the dinucleotide CpG than the rest of DNA. Their unmethylated state guarantees the expression of the corresponding housekeeping genes. At present, the mechanism by which CpG islands remain protected from methylation is not clear. However, some results suggest that poly(ADP-ribosyl)ation, an enzymatic process that introduces a postsynthetic modification onto chromatin proteins, might be involved. Here we show in L929 mouse fibroblast cells that inhibition of poly(ADP-ribose) polymerase(s) at different cell-cycle phases increases the mRNA and protein levels of the major maintenance DNA methyltransferase (DNMT1) in G1/S border. Increase of DNMT1 results in a premature PCNA-DNMT1 complex formation, which facilitates robust maintenance, as well as de novo DNA methylation processes during the G1/S border, which leads to abnormal hypermethylation.
Zardo
Giuseppe
G
Department of Cellular Biotechnologies and Haematology, University of Rome La Sapienza, Rome, Italy.
Reale
Anna
A
Passananti
Claudio
C
Pradhan
Sriharsa
S
Buontempo
Serena
S
De Matteis
Giovanna
G
Adams
Roger L P
RL
Caiafa
Paola
P
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D018899:CpG Islands; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D008957:Models, Genetic; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011233:Precipitin Tests; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation
D001549:Benzamides; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; C025160:3-aminobenzamide; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse