Periodic Report Summary 1 - ONCOMIRNA-BIOGENESIS (Biogenesis of oncogenic microRNAs: from the structure of the microRNA processing complexes to the inhibition of the maturation of human oncogenes)
The growth, function and death of cells in multi-cellular organisms such as in humans need to be tightly controlled. Key to these are the mechanisms for accessing and utilising the information stored in our genomes. One recently identified system which regulates many different cellular processes, involves ribonucleic acid (RNA), a versatile polymer made from different combinations of 4 repeating units. A large array of these regulatory RNA molecules has been identified including some which are implicated in cancers. Indeed, measuring the cellular levels of these molecules can be a useful cancer diagnostic. Cells produce each of these RNA molecules using the same biosynthetic system. My research has revealed atomic resolution insights into factors that define how these molecules are produced. If we can understand the common and unique themes we could use this information to design molecules that selectively inhibit the synthesis of oncogenic RNA regulators implicated in the development of cancers.
MicroRNAs (miRNAs) are a recently identified class of small non-coding RNAs that are believed to regulate the expression of up to 30 % of human genes. The contribution of miRNAs in gene regulation is gaining considerable attention, particularly given the growing links between miRNA misfunction or expression and disease. To date, around 800 - 1 000 miRNAs have been discovered or predicted in humans. The importance of their role in cellular regulation is evidenced by the genes they regulate (p53, pten, retinoblastoma, ras, etc.), the processes they control (cell cycle, angiogenesis, apoptosis, etc.), and the diseases to which their malfunction have been associated. A clear link exists between miRNA misfunction and cancer. Certain miRNAs have been shown to have oncogene-like or tumour suppressor-like activities. Changes in the activity or cellular levels of certain miRNAs have been implicated in different leukemias and lymphomas, and breast, lung, brain, colon and pancreatic cancers (to name a few).
Mature miRNAs are 20 - 25 nucleotide single-stranded molecules that function in association with the protein complex, RISC. The majority of miRNAs are genome-encoded and expressed as long 1-2 kilobase (kb) RNA primary miRNA (pri-miRNA) transcripts. The final miRNA sequence is located in the pri-miRNA and excised in a 2-step process performed by two RNase III-containing protein complexes. The first step is performed by Drosha in the nucleus and the second by Dicer in the cytoplasm. Each processing enzyme is associated with one or more accessory proteins. Almost all known miRNAs pass through this processing pathway making miRNA biogenesis an important research focal point. The basic miRNA biogenesis pathway has been mapped out and the three-dimensional (3D) structures of several of the components have been elucidated. However, despite this work, many of the underlying mechanisms remain unclear. An atomic resolution understanding the molecular basis of miRNA biogenesis will drive future efforts to externally control the production and, therefore, level and activity of oncogenic miRNAs.
MicroRNAs (miRNAs) are a recently identified class of small non-coding RNAs that are believed to regulate the expression of up to 30 % of human genes. The contribution of miRNAs in gene regulation is gaining considerable attention, particularly given the growing links between miRNA misfunction or expression and disease. To date, around 800 - 1 000 miRNAs have been discovered or predicted in humans. The importance of their role in cellular regulation is evidenced by the genes they regulate (p53, pten, retinoblastoma, ras, etc.), the processes they control (cell cycle, angiogenesis, apoptosis, etc.), and the diseases to which their malfunction have been associated. A clear link exists between miRNA misfunction and cancer. Certain miRNAs have been shown to have oncogene-like or tumour suppressor-like activities. Changes in the activity or cellular levels of certain miRNAs have been implicated in different leukemias and lymphomas, and breast, lung, brain, colon and pancreatic cancers (to name a few).
Mature miRNAs are 20 - 25 nucleotide single-stranded molecules that function in association with the protein complex, RISC. The majority of miRNAs are genome-encoded and expressed as long 1-2 kilobase (kb) RNA primary miRNA (pri-miRNA) transcripts. The final miRNA sequence is located in the pri-miRNA and excised in a 2-step process performed by two RNase III-containing protein complexes. The first step is performed by Drosha in the nucleus and the second by Dicer in the cytoplasm. Each processing enzyme is associated with one or more accessory proteins. Almost all known miRNAs pass through this processing pathway making miRNA biogenesis an important research focal point. The basic miRNA biogenesis pathway has been mapped out and the three-dimensional (3D) structures of several of the components have been elucidated. However, despite this work, many of the underlying mechanisms remain unclear. An atomic resolution understanding the molecular basis of miRNA biogenesis will drive future efforts to externally control the production and, therefore, level and activity of oncogenic miRNAs.