t(8;21)(q22;q22) Fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression.
Chromosome abnormalities are frequently associated with cancer development. The 8;21(q22;q22) chromosomal translocation is one of the most common chromosome abnormalities identified in leukemia. It generates fusion proteins between AML1 and ETO. Since AML1 is a well-defined DNA-binding protein, AML1-ETO fusion proteins have been recognized as DNA-binding proteins interacting with the same consensus DNA-binding site as AML1. The alteration of AML1 target gene expression due to the presence of AML1-ETO is related to the development of leukemia. Here, using a 25-bp random double-stranded oligonucleotide library and a polymerase chain reaction (PCR)-based DNA-binding site screen, we show that compared with native AML1, AML1-ETO fusion proteins preferentially bind to DNA sequences with duplicated AML1 consensus sites. This finding is further confirmed by both in vitro and in vivo DNA-protein interaction assays. These results suggest that AML1-ETO fusion proteins have a selective preference for certain AML1 target genes that contain multimerized AML1 consensus sites in their regulatory elements. Such selected regulation provides an important molecular mechanism for the dysregulation of gene expression during cancer development.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92093, USA.
Akiko J
AJ
Okumura
Luke F
LF
Peterson
Fumihiko
F
Okumura
Anita
A
Boyapati
Dong-Er
DE
Zhang
D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D015723:Gene Library; D006801:Humans; D009841:Oligonucleotides / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein; D012091:Repetitive Sequences, Nucleic Acid; D014178:Translocation, Genetic
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human