Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing
Tatsuya Nakamura1, Eli Canaani, Carlo M Croce
1*Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210.
Summary
All1 fusion proteins in leukemia recruit the Drosha enzyme, enhancing microRNA (miRNA) production. This mechanism explains specific miRNA upregulation in cancers driven by these fusions.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- MicroRNAs (miRNAs) are small noncoding RNAs regulating gene expression.
- Aberrant miRNA expression is observed in human malignancies.
- Mechanisms driving cancer-specific miRNA profiles remain largely unclear.
Purpose of the Study:
- To investigate the mechanisms of miRNA dysregulation in leukemias associated with ALL-1 (also known as MLL) gene fusions.
- To identify specific miRNAs upregulated in these leukemias.
- To explore the role of ALL-1 fusions in miRNA biogenesis.
Main Methods:
- Coimmunoprecipitation assays to detect interactions between ALL-1 fusions and Drosha.
- DNase I treatment to assess the nature of the interaction.
- Chromatin immunoprecipitation (ChIP) experiments to evaluate Drosha recruitment to miRNA genes.
Main Results:
- Identification of specific miRNAs upregulated in leukemias with ALL-1 fusions.
- Demonstration of coimmunoprecipitation between ALL-1/Af4 and ALL-1/Af9 fusions and Drosha.
- Evidence of ALL-1 fusion protein-mediated recruitment of Drosha to miRNA gene targets.
Conclusions:
- ALL-1 fusion proteins interact with Drosha, a key enzyme in miRNA biogenesis.
- This interaction leads to the recruitment of Drosha to miRNA gene loci.
- The recruitment of Drosha by ALL-1 fusions is a potential mechanism for the observed upregulation of specific miRNAs in these leukemias.
Related Concept Videos
01:22MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns (non-coding regions of a gene) or intergenic regions (stretches of DNA present between genes). Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself, forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA...
01:22MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA ends...
01:22MicroRNAs
MicroRNA (miRNA) are short, regulatory RNA transcribed from introns—non-coding regions of a gene—or intergenic regions—stretches of DNA present between genes. Several processing steps are required to form biologically active, mature miRNA. The initial transcript, called primary miRNA (pri-mRNA), base-pairs with itself forming a stem-loop structure. Within the nucleus, an endonuclease enzyme, called Drosha, shortens the stem-loop structure into hairpin-shaped pre-miRNA. After the pre-miRNA ends...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
01:06Induced Pluripotent Stem Cells
Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic cells are...
Somatic cells are...
02:15Experimental RNAi
RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...