Nishikura's team demonstrated that two RNA editing enzymes known as ADAR1 and ADAR2, long the focus of study in her laboratory, are able to alter a specific occurrence of the nucleotide adenosine, changing it to inosine in the precursor molecule for miRNA-142, expressed in hematopoietic tissues. This editing had the effect of preventing a key miRNA processing enzyme called Drosha from cutting the precursor miRNA molecule at a critical step in that process.
Looking downstream along the miRNA processing pathway, the scientists also discovered that a molecular complex called RISC played a surprising role. Several components of RISC are known to be involved in normal miRNA processing. But the duties of an identified component of RISC called Tudor-SN were not known. In this study, Tudor-SN was found to be responsible for degrading miRNAs that had been edited in the earlier step, snipping into smaller bits the now useless precursor miRNA molecule precisely at the inosine site resulting from the earlier editing.
Taken together, the results of the study suggest that regulation of the genome is considerably more sophisticated than had been previously understood to be the case.
"People used to think that gene regulation was best done at the very beginning of the production line, which is transcription," says Nishikura. "Therefore, many scientists investigated transcription factors, activating proteins, and so on. But things have changed, and we now know that genes are controlled at many different levels."
The lead author on the Nature Structural & Molecular Biology study is Weidong Yang. Additional Wistar-based co-authors are Thimmaiah P. Chendrimada and Qingde Wang. Ramin Shiekhattar, Ph.D., a professor in two programs at Wistar, the gene expression and regulation program and molecular and cellular oncogenesis pr
Source:The Wistar Institute