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PMID: 11842107 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The MT domain of the proto-oncoprotein MLL binds to CpG-containing DNA and discriminates against methylation.

Nucleic acids research ·Vol. 30 ·No. 4 ·2002-02-15 ·Pages 958-65

Birke M, Schreiner S, García-Cuéllar MP, Mahr K, Titgemeyer F, Slany RK

Abstract

Alterations of the proto-oncogene MLL (mixed lineage leukemia) are characteristic for a high proportion of acute leukemias, especially those occurring in infants. The activation of MLL is achieved either by an internal tandem duplication of 5' MLL exons or by chromosomal translocations that create chimeric proteins with the N-terminus of MLL fused to a variety of different partner proteins. A domain of MLL with significant homology to the eukaryotic DNA methyltransferases (MT domain) has been found to be essential for the transforming potential of the oncogenic MLL derivatives. Here we demonstrate that this domain specifically recognizes DNA with unmethylated CpG sequences. In gel mobility shifts, the presence of CpG was sufficient for binding of recombinant GST-MT protein to DNA. The introduction of 5-methylCpG on one or both DNA strands precluded an efficient interaction. In surface plasmon resonance a KD of approximately 3.3 x 10(-8) M was determined for the GST-MT/DNA complex formation. Site selection experiments and DNase I footprinting confirmed CpG as the target of the MT domain. Finally, this interaction was corroborated in vivo in reporter assays utilizing the DNA-binding properties of the MT domain in a hybrid MT-VP16 transactivator construct.

MeSH Terms
Amino Acid Sequence Base Sequence Binding Sites DNA Footprinting DNA Methylation DNA Modification Methylases/chemistry DNA-Binding Proteins/chemistry,genetics,metabolism Deoxyribonuclease I/chemistry Electrophoretic Mobility Shift Assay Glutathione Transferase/genetics Histone-Lysine N-Methyltransferase Humans Molecular Sequence Data Myeloid-Lymphoid Leukemia Protein Oligodeoxyribonucleotides/metabolism Protein Structure, Tertiary Proto-Oncogene Mas Proto-Oncogene Proteins/chemistry,genetics,metabolism Proto-Oncogenes Recombinant Fusion Proteins/metabolism Substrate Specificity Surface Plasmon Resonance Transcription Factors Transcriptional Activation
Chemicals
CPG-oligonucleotide DNA-Binding Proteins KMT2A protein, human MAS1 protein, human Oligodeoxyribonucleotides Proto-Oncogene Mas Proto-Oncogene Proteins Recombinant Fusion Proteins Transcription Factors Myeloid-Lymphoid Leukemia Protein DNA Modification Methylases Histone-Lysine N-Methyltransferase Glutathione Transferase Deoxyribonuclease I
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Birke Marco
Department of Genetics, University of Erlangen, Staudtstrasse 5, 91058 Erlangen, Germany.
Schreiner Silke
García-Cuéllar María-Paz
Mahr Kerstin
Titgemeyer Fritz
Slany Robert K
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Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
1362-4962
DOI
10.1093/nar/30.4.958
Published
2002-02-15
Pages
958-65
Language
English
Region
England
NLM ID
0411011
PMCID
PMC100340
Subset
IM
External Links
PubMed source DOI: 10.1093/nar/30.4.958 PMC Full Text View journal details
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