Haiwei SONG received his BSc (1987) in Chemistry from Henan University, MSc (1990) in Molecular Biology from the Institute of Biophysics, China and PhD (1998) in Molecular Biology in Leeds University, UK. He worked as a Postdoctoral Research Associate in the Laboratory of Molecular Biophysics in Oxford University and Institute of Cancer Research in London before he joined the ex-Institute of Molecular Agrobiology in Singapore as a Principal Investigator in 2001. He moved to IMCB in 2002 and is currently a Research Director/Professor.

Dr. Song’s laboratory is interested in studying structure and function of proteins and complexes implicated in human diseases such as genetic and neurological disorders as well as cancers. His current research aims to determine the structures of proteins involved in RNA metabolism and human diseases and proteins involved in the Hippo signaling pathway. 

RNA metabolism and human diseases
Multiple cellular functions and pathways are controlled by protein-coding, non-coding RNAs and the RNA-binding proteins associated with them, which form the ribonucleoprotein complexes (RNPs). Mutations that disrupt the functions of RNAs and RNPs are the underlying cause of numerous human diseases. The study of RNA metabolism offers many new opportunities for novel diagnostic and therapeutic intervention. 

(1) Nonsense-mediated mRNA decay

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that recognizes and degrades aberrant mRNAs that have acquired premature translation termination codons due to failure in mRNA processing or genetic mutation. There are around 200 human genetic diseases that result from the premature translation termination. Studies of the proteins required for NMD may lead to rational approaches for the treatment of these genetic disorders. An important step in NMD is the translation-dependent recognition of transcripts with aberrant termination events and then targeting those mRNAs for destruction. In NMD, mRNAs with premature termination codons are degraded either by deadenylation-independent decapping (5'-3' NMD) or by accelerated deadenylation (3'-5' NMD) pathways. The NMD pathway depends on a set of three conserved proteins Upf1, Upf2 and Upf3 that modulate both transcript stability and translation termination efficiency. The key member of this protein set is Upf1, which recognizes aberrant translation termination events by interacting with release factors eRF1 and eRF3, and then in a subsequent step, interacts with Upf2 and Upf3 to trigger degradation of mRNA. We have determined the crystal structure of the catalytic core of human Upf1. Our future goal is to determine the crystal structure of eRF1/eRF3/Upf1 to understand the molecular basis of interplay between premature translation termination and NMD.

(2) Distal Spinal Muscular Atrophy type 1 (DSMA1)

Distal spinal muscular atrophy type 1 (DSMA1) is an autosomal recessive disorder resulting from the degeneration of α-motoneurons in the spinal cord. It manifests itself in early childhood and is characterized by early respiratory failure due to diaphragmatic paralysis. DSMA1 is caused by genetic mutations in the Ighmbp2 gene, which encodes immunoglobulin µ-binding protein 2 (Ighmbp2). The precise cellular function of Ighmbp2 remains elusive, although it has been implicated in transcription and pre-mRNA processing and more recently has been functionally linked to translation. Ighmbp2 is a multidomain protein composed of a DNA/RNA-helicase domain and an R3H domain and a zinc-finger domain and belongs to a subfamily of the Upf1-like group within the helicase superfamily 1 (SF1). We have solved the crystal structures of the Ighmbp2 helicase core with and without bound RNA. Mapping of the pathogenic mutations of DSMA1 onto the helicase core structure provides a molecular basis for understanding the disease causing consequences of Ighmbp2 mutations.