Professor Yanli Liu of our college published a research article in Nature Communications

Survival of motor neuron (SMN), a Tudor domain-containing protein, is encoded by two highly conserved genes,SMN1andSMN2. Homozygous deletion or mutation ofSMN1coupled with a single nucleotide substitution at position 6 of exon 7 (C6T) ofSMN2is responsible for spinal muscular atrophy (SMA), the most common genetic cause of infant death with a frequency of 1 in ~10,000 births (Fig. 1).

Fig. 1 Relationship between SMN and SMA.

Functional studies indicated that SMN,a core component of the SMN complex, is essential for the biogenesis of small nuclear ribonucleoproteins (snRNPs) by assembling the heptameric Sm ring onto spliceosomal snRNA. The Tudor domain of SMN binds to arginine symmetric-dimethylated (Rme2s) Sm proteins, and this interaction plays a critical role in snRNP assembly. SMN also interacts with symmetric-dimethylated R1810 at the C-terminal domain (CTD) of RNA polymerase II (RNAP II) subunit POLR2A (R1810me2s-POLR2A) via its Tudor domain to regulate transcription termination. In SMA patients, abnormal transcription termination, such as the pause of RNAP II and R-loop (DNA-RNA hybrids) accumulation in the termination region, may facilitate neurodegeneration.

In spite of the extensive study of SMN and its associated SMA disease, it is still unclear how SMN protects motor neurons in the spinal cord against degeneration. High-affinity and high-specificity small-molecule probes are effective means to study protein function without changing protein expression.

For this aim, Yanli Liu from our college collaborated with Jinrong Min from theUniversity of Toronto to set out to design SMN-selective chemical probes that would specifically occupy the methylarginine binding pocket and disrupt the Tudor domain-mediated and arginine methylation-dependent interactions. They identified compound1(Cmpd1), a 2.6 μMantagonist for the Tudor domain of SMN (Fig. 2a-b), and determined the SMN-Cmpd1complex structure, which indicates that Cmpd1occupies and competes with Rme2s for the binding pocket of SMN (Fig. 2c). Various on-target engagement assays support that Cmpd1specificallyrecognizesSMN in a cellular context (Fig. 2d-e)and preventsthe interaction of SMN with the R1810me2s of RNA polymerase II subunit POLR2A (Fig. 2f), resulting in disruption of SMN gene occupancy (Fig. 2g-h), transcription termination and R-loop accumulation mimickingSMNdepletion (Fig. 2i-j). Thus, in addition to the antisense, RNAi, and CRISPR/Cas9 techniques, potent SMN antagonists could be used as an efficient tool to understand the biological functions of SMN and the molecular etiology of SMA. The associated data of this study has been published byNature communications,2022, 13:5453,PMID: 36114190with the title“A small molecule antagonist of SMN disrupts the interaction between SMN and RNAP II”. Yanli Liu is the first and co-corresponding author of this paper.

Fig. 2 Discovery and functional study of SMN antagonist, Cmpd1.

This work was supported by the National Key R&D Program of China (2019YFA0802401), the NSERC grant RGPIN-2021-02728, the National Natural Science Foundation of China (31500615 and 81773608), Jiangsu Key Laboratory of Neuropsychiatric Diseases, the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Yanli Liu, a professor at theCollege of Pharmaceutical Sciences,Soochow University, majors in structural and functional studies of epigenetic-associated biomacromolecules and structure-based drug discovery. As the first/co-first/corresponding author, she has published 24 papers in journals such asNature Communications(3),Nature Chemical Biology(1),Nature Chemical Biology(1),Journal of Medicinal Chemistry(1),Pharmacology & Therapeutics(1),Journal of Biological Chemistry(3).