The Argonaute (AGO) Protein Family and small RNAs

A large portion of our genome is transcribed into non-coding RNAs (ncRNAs), which performs various other functions that we are just beginning to explore. One such function of these ncRNAs is in regulation of gene expression of the coding mRNAs. To do so they take the help of specialized catalytic proteins from Argonaute Protein Family. The word ‘Argonaut’ comes from Greek mythology, defines an adventurer engaged in a quest usually by sea, and the term ‘Argo‘ stands for a ship or carrier. Members of this family of proteins are key players in the gene-silencing pathways guided by 3 classes of small RNAs that target mRNA molecules for silencing and destruction. They are:

1. siRNA –  Short-interfering RNAs
2. miRNA – Micro RNAs
3. piRNA – Piwi-interacting RNAs

All of these 3 classes of ncRNAs must associate with a member of ‘Argonaute’ protein for activity. The Argonaute proteins sometimes display endonuclease activity against the mRNA strands that share complementarity with their bound small RNAs. This is called Slicer activity that forms part of the catalytic component of RNA induced silencing complex (RISC) mediated gene silencing known as RNA interference (RNAi).

CLIP-Seq or HITS-CLIP (High throughput sequencing ‘of RNA isolated’ by Cross-linking Immunoprecipitation) technique is a method of mapping genome-wide protein-RNA binding sites in vivo. This method enables identification of miRNA targets and binding sites with single nucleotide resolution.

Because of the capacity of microRNAs to silence or regulate the activity of particular genes, it comes as no surprise that miRNA expression was found to be deregulated in cancers or disease processes, implicating a functional role of miRNAs in the disease development. Previously scientists and Pharma companies just looked for secreted proteins or metabolites in blood or other body fluids in particular diseased conditions, as potential biomarkers to develop diagnostic tests/kits for detection of disease. However,  more recently miRNAs were also detected in cell-free serum, and these circulating miRNAs, can act as potential biomarkers for disease and help distinguish diseased from healthy individuals. The noninvasive nature of circulating miRNA collection and their sensitivity and specificity in diseases has encouraged a pursuit of miRNA biomarker research. As a result, approximately 100 circulating miRNAs have been identified as biomarkers for different diseases, and their number has been growing ever since. This recent discovery warrants an extensive investigation to further elucidate their precise role in malignancy and the potential for improving the current prognostic tools.

Futher Reading:

1. Argonaute proteins at a glance. http://jcs.biologists.org/content/123/11/1819.full
2.  “Mapping in vivo protein-RNA interactions at single-nucleotide resolution from HITS-CLIP data.” Nature Biotechnology 29 (7): 607–614. doi:10.1038/nbt.1873. PMID 21633356. Zhang,C. and Darnell,R.B. (2011).
3. Small RNAs have a large impact: Circulating microRNAs as biomarkers for human diseases. RNA Biol. 2012 Jun 1; 9(6). Weiland M, Gao XH, Zhou L, Mi QS.
4. RNA interference: MicroRNAs as biomarkers.  Nature. 2010 Apr 22;464(7292):1227.
5. MicroRNAs as Novel Biomarkers for Breast Cancer. http://www.hindawi.com/journals/jo/2010/950201/
6. Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies. Cancer Prev Res; 5(3); 492–7. ©2011 AACR