Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal...

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Bibliographic Details
Published in:	Oncogene Vol. 26; no. 38; pp. 5553 - 5563
Main Authors:	OSTLER, K. R, DAVIS, E. M, PAYNE, S. L, GOSALIA, B. B, EXPOSITO-CESPEDES, J, LE BEAU, M. M, GODLEY, L. A
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing 16-08-2007 Nature Publishing Group
Subjects:	Alternative Splicing Analysis Biological and medical sciences Blotting, Western Cancer Cancer cells Cell Line Cell Line, Tumor Cell physiology Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cluster Analysis CpG islands CpG Islands - genetics Deoxyribonucleic acid DNA DNA (Cytosine-5-)-Methyltransferases - genetics DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation DNA Methyltransferase 3B DNA microarrays Fundamental and applied biological sciences. Psychology Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Genetics Humans Isoforms Leukemia Methylation Molecular and cellular biology Neoplasms - genetics Neoplasms - pathology Oligonucleotide Array Sequence Analysis Protein Isoforms - genetics Protein Isoforms - metabolism Proteins Reverse Transcriptase Polymerase Chain Reaction Transcription Transcription, Genetic Transfection Tumor cell lines Tumor suppressor genes Tumors United States Splicing aberrant mRNA splicing Malignant tumor Gene expression Carcinogenesis Protein Messenger RNA DNA Epigenetics DNA methylation DNMT3B Methylation Cancer
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Summary:	Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5' end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Department of Biology, Elmhurst College, 190 Prospect Ave., Elmhurst, IL 60126, USA.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/sj.onc.1210351