[2] mRNA quality control

We are interested in how the pathways dealing with synthesis and turnover of messenger RNAs shape genomes and transcriptomes.

To NMD or not to NMD? About ⅓ of heritable genetic diseases, and the majority of tumors, result from truncating mutations affecting disease genes. This makes the nonsense-mediated mRNA decay (NMD) pathway an important player in shaping disease phenotypes. We analyzed thousands of sequences of human tumor genomes and transcriptomes, to infer how the quality control pathway of nonsense-mediated mRNA decay (NMD) decides which mRNAs to degrade (Lindeboom et al. 2016 Nat Genet). Next, we used these rules of NMD to reveal patterns of positive and negative selection on tumor suppressor genes and on essential genes in cancers.

Dr. Jekyll and Mr. Hyde. The NMD pathway is normally seen as protective (e.g. it can clean up aberrant splicing products). By analyzing distributions of pathogenic germline variants in human populations, we however suggest that the converse is the case. In the majority of genetic diseases NMD is more likely to aggravate disease phenotypes (Lindeboom et al. 2019 Nat Genet). This opens the possibility of using NMD inhibitors to treat a variety of genetic diseases. This includes also cancer, where NMD often downregulates frameshifted mRNA and so inhibiting NMD may potentiate immunotherapy (Lindeboom et al. 2019 Nat Genet). Finally, we think that NMD can affect the outcomes of CRISPR/Cas9 gene editing and so should be considered in reagent design.

Not what it says on the box. Cancer cell lines are often used as easy-to-handle models of tumors. We 'aligned' transcriptomes of ~600 common cell lines with ~10,000 tumors to find instances of common cell lines labelled with the incorrect tissue-of-origin (Salvadores et al. 2020 Sci Adv). Using cell lines that closely match the cancer-of-origin improves ability to identify targeted drugs.

(figure from Lindeboom et al. 2016 Nat Genet showing the rules of NMD, and their implications to mutations occurring in cancer genes)

for more information, see also our review article: Nonsense-Mediated mRNA Decay in Cancer and Other Genetic Diseases. Supek, Lehner and Lindeboom (2020) Trends in Genetics.

"Try not. Do… or do not. There is no try." -- Yoda.