This week we profile a recent publication in Nature Chemical Biology from the lab of Dr. Heidi Greulich (pictured) at the Broad Institute and Dana-Farber Cancer Institute.
Can you provide a brief overview of your lab’s current research focus?
Our group is interested in understanding the mechanism of action of velcrin compounds, which kill cancer cells expressing elevated levels of PDE3A and SLFN12 by inducing PDE3A-SLFN12 complex formation, which in turn upregulates the RNase activity of SLFN12. We are also interested in leveraging the PDE3A-SLFN12 interaction to develop a cancer therapeutic.
What is the significance of the findings in this publication?
In our recent publication in Nature Chemical Biology, we reported the discovery of the physiological substrate of the SLFN12 RNase, tRNA-Leu-TAA. We furthermore showed that velcrin-induced PDE3A-SLFN12 complex formation results in tRNA-Leu-TAA cleavage, stalling of ribosomes at cognate TTA codons on mRNA, and global inhibition of protein synthesis, ultimately causing cancer cell death.
What are the next steps for this research?
In the next steps for our research, we will dissect the biochemical details of tRNA-Leu-TAA cleavage by SLFN12. We would also like to understand the physiological function of SLFN12.
